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1.  The Influence of Genetics on Response to Treatment with Ranibizumab (Lucentis) for Age-Related Macular Degeneration: The Lucentis Genotype Study (An American Ophthalmological Society Thesis) 
Age-related macular degeneration (AMD) has a complex etiology arising from genetic and environmental influences. This past decade have seen several genes associated with the disease. Variants in five genes have been confirmed to play a major role. The objective of this study was to evaluate whether genes influence treatment response to ranibizumab for neovascular AMD. The hypothesis was that an individual’s genetic variation will determine treatment response.
The study was a two-site prospective open-label observational study of patients newly diagnosed with exudative (neovascular) AMD receiving intravitreal ranibizumab therapy. Treatment-naïve patients were enrolled at presentation and received monthly “as needed” therapy. Clinical data was collected monthly and DNA extracted. Genotyping was performed using the Illumina (San Diego, California) 660-Quad single-nucleotide polymorphism (SNP) chip. Regression analyses were performed to identify SNPs associated with treatment-response end points.
Sixty-five patients were enrolled. No serious adverse events were recorded. The primary outcome measure was change in ETDRS visual acuity at 12 months. A SNP in the CFH gene was found to be associated with less improvement in visual acuity while receiving ranibizumab therapy. The C3 gene, among others, was associated with reduced thickening and improved retinal architecture. VEGFA, FLT1, and CFH were associated with requiring fewer ranibizumab injections over the 12-month study.
This study is one of the first prospective pharmacogenetic study of intravitreal ranibizumab. Although preliminary, the results identify a number of putative genetic variants, which will be further examined by replication and functional studies to elucidate the complete pharmacogenetic architecture of therapy for AMD.
PMCID: PMC3259677  PMID: 22253485
2.  Pharmacogenetic Influence of LOC387715/HTRA1 on the Efficacy of Bevacizumab Treatment for Age-Related Macular Degeneration in a Korean Population 
The purpose of this study was to determine the pharmacogenetic effects of complement factor H (CFH) Y402H, LOC387715 and high-temperature requirement factor A1 (HTRA1) genotypes on the treatment of exudative age-related macular degeneration (AMD) by intravitreal bevacizumab injection in a Korean population.
Seventy-five patients diagnosed with exudative AMD were treated with intravitreal bevacizumab (2.5 mg) monotherapy. All patients received three initial intravitreal bevacizumab injections every four weeks and were then treated "as needed" based on clinical findings, optical coherence tomography and fluorescein angiography during the 12 month follow-up period after the third injection.
The difference in visual acuity improvement among the three genotypes of LOC387715 were statistically significant at six months post-treatment (logarithm of the minimum angle of resolution; TT, 0.346; GT, 0.264; GG, 0.188; p = 0.037). Among the LOC387715 genotypes, the number of additional injections was lower in patients who had the risk T allele (GG, 2.143; GT, 2.000; TT, 1.575; p = 0.064). There was no significant difference between visual acuity and central macular thickness change in the CFH Y402H polymorphism group during the 12 month follow-up period. However, the TC group of CFH Y402H required more additional bevacizumab injections than the TT group (TT, 1.517; TC, 3.363; p = 0.020).
This study demonstrated that different LOC387715/HTRA1 genotypes resulted in different bevacizumab treatment responses on exudative AMD. Patients with the risk allele had an improved treatment response and less need for additional injections. However, patients with the CFH Y402H risk allele needed more additional injections of bevacizumab in order to improve visual acuity. This study illustrates how pharmacogenetic factors may help determine treatment modality and dosing. This could ultimately provide basic data for 'personalized medicine' in AMD.
PMCID: PMC3506814  PMID: 23204795
Bevacizumab; Complement factor H Y402H; HTRA1; LOC387715; Macular degeneration
3.  Pharmacogenetic association with early response to intravitreal ranibizumab for age-related macular degeneration in a Korean population 
Molecular Vision  2013;19:702-709.
To determine whether genetic factors that influence age-related macular degeneration (AMD) have an early pharmacogenetic effect on treating exudative AMD with ranibizumab in a Korean population.
A retrospective study of 102 patients (70 with typical neovascular AMD and 32 with polypoidal choroidal vasculopathy) with exudative AMD treated with intravitreal ranibizumab monotherapy was conducted. Optical coherence tomography, fluorescein, and indocyanine green angiography were taken at the baseline. The best-corrected visual acuity (BCVA) and the central subfield macular thickness (CSMT) were recorded at the baseline and at each monthly visit. The genotypes of the polymorphisms in the known AMD susceptibility loci (CFH, AMRS2, HTRA1, VEGFA, and KDR) were determined, and association between their frequencies and the changes in the BCVA and the CSMT were evaluated.
The mean baseline visual acuity was 0.96±0.59 logMAR (approximately 20/200 in the Snellen equivalent), and the mean number of injections was 3.87 before the month 6 visit. No association was observed between the change in BCVA and each genotype. For the changes in the CSMT, a significant difference was observed only with the VEGF-A (rs833069) gene. The decrease in the CSMT at month 3 for the major allele homozygote AA genotype, the heterozygote AG genotype, and the risk allele homozygote GG genotype was 25.66±85.40, 86.93±92.31, and 85.30±105.30 μm, respectively (p=0.012, p=0.044, and p=0.002 for AG, GG, and combined AG or GG genotype, respectively, compared to the AA genotype). This trend was maintained until month 6.
The VEGF-A (rs833069) polymorphism showed a significant association with the anatomic response to intravitreal ranibizumab. No significant difference was found between the genotype of the potential risk polymorphism for development of AMD and the early visual improvement after intravitreal ranibizumab.
PMCID: PMC3611944  PMID: 23559864
4.  The effect of CFH polymorphisms on the response to the treatment of age-related macular degeneration (AMD) with intravitreal ranibizumab 
Molecular Vision  2013;19:2571-2578.
The purpose of this study is to evaluate the effect of complement factor H (CFH) Y402H CC and TT polymorphisms on treatment response to intravitreal ranibizumab injection in patients with wet age-related macular degeneration (AMD).
One hundred ninety-three patients with choroidal neovascularization (CNV) secondary to AMD who were monitored for at least 6 months of follow-up, and with at least three ranibizumab injections, were included in the study. At the final examination, an increase in visual acuity (VA) of five letters or more compared to the initial VA was regarded as a good response, and a decrease in VA of five letters or more compared to the initial VA was evaluated as a poor response. A genetic examination was performed with a PCR melting curve analysis. In the statistical evaluation, SPSS version 18 software was used.
The mean age of the patients was 71.01 (55–86) years, the mean follow-up was 13.34 (6–36) months, and the mean number of injections was 4.02 (3–15). There were 96 patients in the good response group (Group 1) and 97 patients in the poor response group (Group 2). The initial VA in Group 1 was 41.34 (10–64) letters, the initial central macular thickness (CMT) was 213.40 (126–494) µm, and the initial lesion width was 3760 (1430–6430) µm. The initial VA in Group 2 was 52.89 (26–82) letters, the initial CMT was 257.60 (115–882) µm, and the initial lesion width was 4460 (1000–7650) µm. There was no statistically significant difference between the two groups in terms of the initial VA and CMT (p=0.094, p=0.083). However, there was a statistically significant difference between the groups in the width of the initial lesion (p=0.003). In Group 1, 15 CC, 30 TT, and 51 TC alleles were found, and in Group 2, 49 CC, two TT, and 46 TC alleles were found, and the distribution was significantly different between the two groups (p=0.012). The change in the distribution of genotypes was not associated with either the lesion size or VA (p=0.841). Fibrosis developed in 12 patients who were all poor responders.
CFH Y402H CC accompanied a poor response, and TT accompanied a good response in this series of patients with AMD undergoing ranibizumab therapy.
PMCID: PMC3869644  PMID: 24367156
5.  Pharmacogenetics for Genes Associated with Age-Related Macular Degeneration (AMD) in the Comparison of AMD Treatments Trials (CATT) 
Ophthalmology  2013;120(3):593-599.
To evaluate the pharmacogenetic relationship between genotypes of single nucleotide polymorphisms (SNPs) known to be associated with age-related macular degeneration (AMD) and response to treatment with ranibizumab (Lucentis) or bevacizumab (Avastin) for neovascular AMD.
Clinical trial.
834 (73%) of 1149 patients participating in the Comparison of AMD Treatments Trials (CATT) were recruited through 43 CATT clinical centers.
Each patient was genotyped for SNPs rs1061170 (CFH), rs10490924 (ARMS2), rs11200638 (HTRA1), and rs2230199 (C3), using TaqMan SNP genotyping assays.
Main Outcomes Measures
Genotypic frequencies were compared to clinical measures of response to therapy at one year including mean visual acuity (VA), mean change in VA, ≥15 letter increase, retinal thickness, mean change in total foveal thickness, presence of fluid on OCT, presence of leakage on fluorescein angiography (FA), mean change in lesion size and mean number of injections administered. Differences in response by genotype were evaluated with tests of linear trend calculated from logistic regression models for categorical outcomes and linear regression models for continuous outcomes. To adjust for multiple comparisons, p≤0.01 was considered statistically significant.
No statistically significant differences in response by genotype were identified for any of the clinical measures studied. Specifically, there were no high-risk alleles that predicted final VA or change in VA, the degree of anatomical response (fluid on OCT or FA, retinal thickness, change in total foveal thickness, change in lesion size) or the number of injections. Furthermore, a stepwise analysis failed to show a significant epistatic interaction among the variants analyzed; i.e., response did not vary by the number of risk alleles present. The lack of association was similar whether patients were treated with ranibizumab or bevacizumab or whether they received monthly or pro re nata (PRN) dosing.
Although specific alleles for CFH, ARMS2, HTRA1 and C3 may predict the development of AMD, they did not predict response to anti-vascular endothelial growth factor (VEGF) therapy.
PMCID: PMC3633658  PMID: 23337555
6.  Pharmacogenetic associations with long-term response to anti-vascular endothelial growth factor treatment in neovascular AMD patients 
Molecular Vision  2014;20:1680-1694.
To investigate the pharmacogenetic associations between the genetic risk variants of age-related macular degeneration (AMD) and long-term outcome after intravitreal anti-vascular endothelial growth factor (VEGF) treatment in Korean neovascular AMD patients.
This prospective study included 394 treatment-naïve patients (394 eyes) that underwent intravitreal anti-VEGF treatment for neovascular AMD for at least 12 months. Patients were genotyped for 17 single nucleotide polymorphisms within 13 AMD-relevant genes. Initially, patients underwent three monthly injections of intravitreal ranibizumab and were retreated as needed with ranibizumab or bevacizumab. For each candidate polymorphism, genotypic associations with treatment outcome measures at months 12 and 24, including mean change in best-corrected visual acuity (BCVA) from baseline, visual gain of ≥15 letters, mean change in central subfield macular thickness (CSMT) from baseline on spectral domain optical coherence tomography (OCT), presence of fluid on OCT, and mean number of injections, were investigated using logistic or linear regression models with adjustment for non-genetic covariates.
At month 24, BCVA improved by 4.5 ± 22.5 letters and CSMT decreased by 69.4 ± 112.6 µm from baseline. Regression analysis with Bonferroni correction showed that the TT genotype for VEGFA rs3025039 was associated with a significantly higher chance of a visual gain of ≥15 letters at month 24 than other genotypes (odds ratio, 4.57; 95% confidence interval, 1.89 - 11.1; corrected p = 0.0434). As for tomographic outcome, the minor allele homozygotes for ARMS2 rs10490924 and HTRA1 rs1100638 (GG genotype for both) were associated with a larger CSMT reduction at month 12 than other genotypes, with borderline significance after Bonferroni correction (118.6 ± 132.7 µm versus 62.7 ± 89.7 µm, corrected p = 0.0656 for rs10490924; 115.7 ± 131.7 µm versus 63.6 ± 89.8 µm, corrected p = 0.0528 for rs11200638). No polymorphism showed a significant association with the number of injections.
In this Korean neovascular AMD cohort, treatment outcome after anti-VEGF was found to differ by the genotypes of VEGFA rs3025039, ARMS2 rs10490924, and HTRA1 rs11200638. Given more evidence of pharmacogenetic associations with the anti-VEGF agent, individualized therapeutic approaches based on genetic background could lead to optimal treatment in neovascular AMD.
PMCID: PMC4278401  PMID: 25558172
7.  Association of CFH, LOC387715, and HTRA1 polymorphisms with exudative age-related macular degeneration in a northern Chinese population 
Molecular Vision  2008;14:1373-1381.
Variants in complement factor H (CFH), the hypothetical LOC387715, and the high-temperature requirement A-1 (HTRA1) genes have been reported to be associated with age-related macular degeneration (AMD). The purpose of this study was to investigate the association of reported common single-nucleotide polymorphisms (SNPs) in CFH, LOC387715, and HTRA1 with exudative AMD in a northern Chinese population.
A cohort of 121 unrelated patients with exudative AMD and 132 control subjects were enrolled in this study. Genomic DNA was extracted from blood leukocytes. Genotyping for SNPs rs1061170:T>C in CFH (Y402H), rs10490924:G>T in LOC387715 (A69S), and rs11200638:G>A in the promoter of HTRA1 was performed using a polymerase chain reaction (PCR) method followed by allele-specific restriction enzyme digestion and direct sequencing.
The Y402H variant in CFH was not associated with exudative AMD in our study population. Frequencies of Y402H was 10.3% in AMD cases and 8.0% in controls (p=0.353). Significant associations were detected for exudative AMD with SNPs rs10490924:G>T in LOC387715 (A69S), and rs11200638:G>A in the promoter of HTRA1. The risk T-allele frequency of rs10490924 in LOC387715 was 64.9% in cases versus 43.2% in controls (p<0.001). The odds ratio for risk of AMD was 1.56 (95% CI; 0.80–3.03) for the GT genotype and 5.45 (95% CI; 2.59–11.49) for the TT genotype. The A allele frequency of rs11200638 in the HTRA1 promoter was 67.8% in cases versus 42.4% in controls (p<0.001). The odds ratio was 2.75 (95% CI; 1.34–5.64) for the GA genotype and 7.90 (95% CI; 3.61–17.26) for the AA genotype. An odds ratio of 7.94 (95% CI; 3.49–18.04) was obtained for carriers with both TT genotype in LOC387715 and AA genotype in the HTRA1 promoter.
Our data suggest that the LOC387715 and HTRA1 polymorphisms are associated with a higher risk of exudative AMD in northern Chinese. We found no association of CFH Y402H with exudative AMD. The low frequency of CFH Y402H variant was further confirmed in this study population.
PMCID: PMC2493029  PMID: 18682812
8.  Two-year outcomes of pro re nata ranibizumab monotherapy for exudative age-related macular degeneration in Japanese patients 
To describe outcomes of intravitreal ranibizumab using a pro re nata regimen for treatment-naive exudative age-related macular degeneration (AMD), in Japanese patients over the first 2 years.
Clinical records were retrospectively reviewed of 48 eyes of 48 patients with treatment-naive exudative AMD who underwent intravitreal ranibizumab therapy. After three monthly injections (induction), patients were examined monthly, and subsequent injections were performed as needed (pro re nata) for any residual activity, by fundus biomicroscopy and imaging studies, regardless of severity.
Twenty-nine (60%) of the patients were men, and 19 (40%) were women; the mean age was 76.1 years. Of the 48 eyes evaluated, 17 (35%) had findings consistent with polypoidal choroidal vasculopathy, and five (10%) with retinal angiomatous proliferation. A mean of 6.0 ranibizumab injections were given in the first year, 3.5 in the second year, and 9.5 over the 2-year period. The best-corrected visual acuity (logarithm of minimum angle of resolution) improved significantly, from 0.35 at baseline to 0.21 at 12 months (P < 0.01), and remained stable at 0.21 at 24 months (P < 0.01). The mean central macular thickness decreased significantly, from 355.4 μm at baseline to 237.9 μm at 12 months (P < 0.01) and 247.7 μm at 24 months (P < 0.01).
Improved visual acuity and decreased central macular thickness were observed and maintained over a 2-year period, in a Japanese population receiving 3 monthly induction injections followed by a pro re nata regimen of ranibizumab for exudative AMD.
PMCID: PMC3633548  PMID: 23620657
optical coherence tomography; polypoidal choroidal vasculopathy; retinal angiomatous proliferation
9.  CFH, VEGF, and PEDF genotypes and the response to intravitreous injection of bevacizumab for the treatment of age-related macular degeneration 
We determined whether there is an association between complement factor H (CFH), high-temperature requirement A-1 (HTRA1), vascular endothelial growth factor (VEGF), and pigment epithelium-derived factor (PEDF) genotypes and the response to treatment with a single intravitreous injection of bevacizumab for age-related macular degeneration (AMD). Eighty-three patients with exudative AMD treated by bevacizumab injection were genotyped for three single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996) in the CFH gene, a rs11200638-SNP in the HTRA1 gene, three SNPs (rs699947, rs1570360, rs2010963) in the VEGF gene, and four SNPs (rs12150053, rs12948385, rs9913583, rs1136287) in the PEDF gene using a TaqMan assay. The CT genotype (heterozygous) of CFH-rs1061170 was more frequently represented in nonresponders in vision than TT genotypes (nonrisk allele homozygous) at the time points of 1 and 3 months, while there was no CC genotype (risk allele homozygous) in our study cohort (p = 7.66 × 10−3, 7.83 × 10−3, respectively). VEGF-rs699947 was also associated with vision changes at 1 month and PEDF-rs1136287 at 3 months (p = 5.11 × 10−3, 2.05 × 10−2, respectively). These variants may be utilized for genetic biomarkers to estimate visual outcomes in the response to intravitreal bevacizumab treatment for AMD.
PMCID: PMC3148139  PMID: 21811649
Age-related macular degeneration; Bevacizumab; Complement factor H; Genetic biomarker; High-temperature requirement A-1; Pigment epithelium-derived factor; Vascular endothelial growth factor
10.  Neovascular Age-Related Macular Degeneration Risk Based on CFH, LOC387715/HTRA1, and Smoking 
PLoS Medicine  2007;4(12):e355.
Age-related macular degeneration (AMD) is the major cause of blindness in the elderly. Those with the neovascular end-stage of disease have irreversible loss of central vision. AMD is a complex disorder in which genetic and environmental factors play a role. Polymorphisms in the complement factor H (CFH) gene, LOC387715, and the HTRA1 promoter are strongly associated with AMD. Smoking also contributes to the etiology. We aimed to provide a model of disease risk based on these factors.
Methods and Findings
We genotyped polymorphisms in CFH and LOC387715/HTRA1 in a case–control study of 401 patients with neovascular AMD and 266 controls without signs of disease, and used the data to produce genetic risk scores for the European-descent population based on haplotypes at these loci and smoking history. CFH and LOC387715/HTRA1 haplotypes and smoking status exerted large effects on AMD susceptibility, enabling risk scores to be generated with appropriate weighting of these three factors. Five common haplotypes of CFH conferred a range of odds ratios (ORs) per copy from 1 to 4.17. Most of the effect of LOC387715/HTRA1 was mediated through one detrimental haplotype (carriage of one copy: OR 2.83; 95% confidence interval [CI] 1.91–4.20), with homozygotes being at particularly high risk (OR 32.83; 95% CI 12.53–86.07). Patients with neovascular macular degeneration had considerably higher scores than those without disease, and risk of blinding AMD rose to 15.5% in the tenth of the population with highest predicted risk.
An individual's risk of developing AMD in old age can be predicted by combining haplotype data with smoking status. Until there is effective treatment for AMD, encouragement to avoid smoking in those at high genetic risk may be the best option. We estimate that total absence of smoking would have reduced the prevalence of severe AMD by 33%. Unless smoking habits change or preventative treatment becomes available, the prevalence of AMD will rise as a consequence of the increasing longevity of the population.
Anne Hughes and colleagues show that an individual's risk of developing age-related macular degeneration in old age can be predicted by combining haplotype data with smoking status.
Editors' Summary
Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly. The macula is the central region of the retina, the tissue at the back of the eye that converts light into electrical messages and sends them to the brain. In the commonest form of AMD—“dry” AMD—the light-sensitive cells in the macula gradually die. In “wet” or “neovascular” AMD (one in 10 cases of AMD, but responsible for 90% of severe AMD-related blindness), abnormal blood vessels grow below the macula. Fluid leaking out of these vessels dislodges and damages the macula, after which loss of vision occurs rapidly. Both forms of AMD destroy the sharp central vision that is needed for reading and driving, leaving only dim, blurred images or a black hole at the center of vision. Neither form can be cured but with wet AMD the loss of vision can sometimes be slowed or halted if caught early by destroying the new blood vessels with laser surgery or a technique called photodynamic therapy or by blocking their formation by injecting special drugs into the eye.
Why Was This Study Done?
No-one knows what causes AMD but factors that increase a person's risk of developing the disease include increasing age, smoking, being white, and a family history of AMD. Recently, researchers have identified several “polymorphisms” (inherited DNA sequence variations that are common within populations) that are associated with AMD. These polymorphisms are in the complement factor H gene (the scientific symbol for this gene is CFH) and in a gene region called LOC387715/HTRA1. It would be useful to be able to use these risk factors to identify those people at the highest risk of developing neovascular AMD before the disease damages their vision. In this study, the researchers have investigated the association between AMD and polymorphisms in CFH and LOC387715/HTRA1 in more depth. They have then used this new information to build a model of AMD risk that should allow physicians to identify individuals at high risk of developing neovascular AMD.
What Did the Researchers Do and Find?
The researchers catalogued polymorphisms in CFH and LOC387715/HTRA1 in several hundred people with and without neovascular AMD. From these data, they identified three haplotypes (sets of polymorphisms that are inherited as a unit; everyone inherits two copies of each haplotype, one from each parent) in CFH that were more common in people with AMD than in those without and two that were associated with a decreased risk of developing AMD. In LOC387715/HTRA1 they identified one particularly detrimental haplotype. Compared to people without this haplotype, people with one copy of the deleterious haplotype were three times as likely to develop neovascular AMD; people with two copies were thirty times as likely to develop AMD. Smoking history also had a large effect on susceptibility to AMD. The researchers then developed a simple AMD risk scoring system based on CFH and LOC387715/HTRA1haplotypes and smoking status. From this, they calculated that people with the lowest risk scores have a minimal risk of developing AMD whereas about 15% of people with the highest risk scores are likely to develop AMD.
What Do These Findings Mean?
These findings indicate that it is possible to predict an individual's risk of developing AMD in old age by examining a small number of haplotypes and asking about their smoking status. The model developed by the researchers needs to be validated in other groups of people and may have to be modified if other gene variants that affect the risk of AMD are identified. For now, the results of this research provide physicians with a way to identify those individuals at the highest genetic risk of developing AMD so that they can step up their efforts to persuade these people to avoid smoking. In the future, when effective long-term treatments for AMD become available, the scoring system could also help doctors decide which of their elderly patients should be monitored most intensively for the early signs of AMD so that they can be treated before their vision is irreversibly damaged.
Additional Information.
Please access these Web sites via the online version of this summary at
MedlinePlus provides links to information on macular degeneration and an encyclopedia page on macular degeneration (in English and Spanish)
Pages on the US National Institutes of Health NIH SeniorHealth site provides text and speech information about AMD
The US National Eye Institute and the UK Royal National Institute of Blind People also provide information about AMD
PMCID: PMC2222948  PMID: 18162041
11.  Retinal ganglion cell function after repeated intravitreal injections of ranibizumab in patients with age-related macular degeneration 
The purpose of this study was to evaluate the safety of intravitreal ranibizumab injection in patients with age-related macular degeneration.
Materials and methods
We examined retinal ganglion cell function using the photopic negative response of the electroretinogram (ERG) in patients with age-related macular degeneration (AMD) treated with intravitreal injections of ranibizumab. We studied 32 eyes of 32 patients with AMD and aged 50–84 years with a mean of 71 years. An intravitreal ranibizumab injection was given three times at monthly intervals. Additional injections were given according to an optical coherence tomography-guided variable dosing regimen. ERG recordings were made before treatment (baseline) and at 3, 6, 9, and 12 months postoperatively. Full-field cone ERGs were elicited by red stimuli on a blue background. The focal macular ERGs were elicited by a 15 degree white stimulus spot centered on the macular region. We measured the amplitudes of the a and b waves, oscillatory potentials, and the photopic negative response of the full-field cone and focal macular ERGs.
Visual acuity was significantly better than the baseline acuity, and macular thickness was significantly reduced after the intravitreal injections of ranibizumab. The amplitudes and implicit times of each wave of the full-field cone ERGs were not significantly changed after intravitreal ranibizumab injections. However, the amplitudes of each wave of the focal macular ERGs were increased after the injections. The implicit times of the a and b waves of the focal macular ERGs were significantly shortened after intravitreal injections of ranibizumab. The ratio of the full-field and focal photopic negative response/b-wave amplitude was not significantly changed after the injections.
The amplitudes of the focal macular ERGs, including the photopic negative response improved after repeated intravitreal ranibizumab injections, accompanied by a recovery of visual acuity and macular structure. The results of the full-field cone ERGs indicate that retinal ganglion cell function was not altered by repeated intravitreal ranibizumab injection.
PMCID: PMC3413340  PMID: 22888205
age-related macular degeneration; retinal ganglion cell; photopic negative response; electroretinogram; ranibizumab
12.  Incidence of Choroidal Neovascularization in the Fellow Eye in the Comparison of Age-related Macular Degeneration Treatments Trials 
Ophthalmology  2013;120(10):2035-2041.
To assess the influence of drug, dosing regimen, and traditional, non-traditional, and genetic risk factors on the incidence of choroidal neovascularization (CNV) in the fellow eye of patients treated for CNV with ranibizumab or bevacizumab.
Cohort study of patients enrolled in a multicenter randomized clinical trial.
Patients with no CNV in the fellow eye at the time of enrollment in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT).
Eligibility criteria for the clinical trial required that study eyes have evidence on fluorescein angiography and optical coherence tomography (OCT) of CNV secondary to age-related macular degeneration (AMD) and visual acuity between 20/25 and 20/320. Treatment for the study eye was assigned randomly to either ranibizumab or bevacizumab and to three different regimens for dosing over a two-year period. The genotypes for four single nucleotide polymorphisms (SNPS) associated with risk of AMD were determined. Only patients without CNV in the fellow eye at baseline were considered at risk. CATT ophthalmologists examined patients every four weeks through two years and recorded treatment for CNV in the fellow eye.
Main Outcome Measures
Development of CNV in the fellow eye.
Among 1185 CATT participants, 727 (61%) had no CNV in the fellow eye at enrollment. At two years, CNV had developed in 75 (20.6%) of 365 patients treated with ranibizumab and 60 (16.6%) of 362 patients treated with bevacizumab (absolute difference 4.0%, 95% confidence interval (−1.7%, 9.6%); p=0.17). The risk ratio for pro re nata (PRN) dosing relative to monthly dosing was 1.1 (95% confidence interval (0.8, 1.6)). Greater elevation of the retinal pigment epithelium and fluid in the foveal center of the study eye were associated with increased incidence of CNV in the fellow eye. Incidence was not associated with genotype on rs1061170 (CFH), rs10490924 (ARMS2), rs11200638 (HTRA1), and rs2230199 (C3) (p > 0.35).
Through two years, there was no statistically significant difference between ranibizumab and bevacizumab in incidence of CNV in the fellow eye. Genotype on four SNPs previously found to be associated with AMD did not affect the risk of CNV in the fellow eye among CATT patients.
PMCID: PMC3758381  PMID: 23706946
13.  Bevacizumab vs ranibizumab for neovascular age-related macular degeneration in Chinese patients 
To compare the clinical efficacy of intravitreal injections of bevacizumab and ranibizumab for treating Chinese patients with neovascular age-related macular degeneration (AMD).
Among 60 Chinese patients with exudative AMD (60 eyes), 28 received intravitreal bevacizumab injections (1.25mg) and 32 received intravitreal ranibizumab injections (0.5mg), once a month for 3 months and were followed for a total of 6 months. Monthly optical coherence tomography (OCT) was used to determine whether the patients received additional treatments during the follow-up. We compared the baseline and 6-month follow-up values of mean best-corrected visual acuity (BCVA) and central retinal thickness (CRT) in both groups of patients. We also compared the occurrence of adverse events.
At the 6-month follow-up, the mean BCVA (logMAR) of the bevacizumab and ranibizumab treatment groups improved from the baseline measurements of 0.72±0.23 and 0.73±0.22 to 0.47±0.14 and 0.45±0.20, respectively (P<0.05 for both groups). However, the change was not significantly different between the two groups. As evaluated by OCT, CRT decreased from 366.71±34.72µm and 352±36.9µm at baseline to 250.86±41.51µm and 243.22±41.38µm in the bevacizumab and ranibizumab groups, respectively (P<0.05 for both groups). However, the change was not significantly different between the two groups. There were no severe local adverse reactions or systemic adverse events.
Intravitreal bevacizumab and ranibizumab have equivalent effects on BCVA and CRT and appeare safe over the short-term.
PMCID: PMC3633755  PMID: 23638418
age-related macular degeneration; choroidal neovascularization; bevacizumab (avastin); ranibizumab (lucentis)
14.  Effectiveness of ranibizumab intravitreal injections for exudative age-related macular degeneration treatment: 12-month outcomes 
The aim of this paper was to evaluate functional and anatomical results of intravitreal ranibizumab injections and the course of exudative age-related macular degeneration (AMD) treatment over a 12-month observation period.
In 25 patients with active dominantly classic exudative AMD, treatment was performed according to the following schedule: 3 intravitreal injections of 0.5 mg ranibizumab at monthly intervals (saturation phase); further injections were based on activity of the neovascular process. Changes in VA and central retinal thickness (CRT) during treatment were evaluated with ANOVA testing.
Mean pre-treatment best corrected visual acuity was 0.73±0.27 logMAR. After the third ranibizumab injection the best results, 0.54±0.27 logMAR, were seen; 12-month results were 0.58±0.26 logMAR. Patients had a mean improvement of 10.6 letters at 12 months. In 92% of patients stabilization or improvement of vision was observed. The mean number of injections in the 12-month period was 6.
Baseline mean CRT was 351.12±74.15 μm. After the first ranibizumab injection it decreased significantly to 221.96±60.85 μm, after the third injection it was 200.80±47.63 μm, and after 12 months it was 213.16±44.37 μm. Mean correlations between baseline average CRT and baseline average VA measured in ETDRS letters (p=0.017) and in logMAR scale (p=0.033) and between average CRT after the third injection and average VA in logMAR scale after the third injection (p=0.047) were noted.
Treatment with intravitreal ranibizumab injections according to the presented scheme provides AMD patients with a chance of stabilization and improvement of the topical state, with a lower number of injections and preserved topical and general safety. Our results suggest that regular monthly controls are necessary to be able react rapidly to the smallest signs of deterioration, not only in visual acuity, but also in OCT images.
PMCID: PMC3560504  PMID: 21873944
exudative AMD; ranibizumab; central retinal thickness
15.  Ranibizumab and Bevacizumab for Neovascular Age-Related Macular Degeneration 
The New England journal of medicine  2011;364(20):1897-1908.
Clinical trials have established the efficacy of ranibizumab for the treatment of neovascular age-related macular degeneration (AMD). In addition, bevacizumab is used off-label to treat AMD, despite the absence of similar supporting data.
In a multicenter, single-blind, noninferiority trial, we randomly assigned 1208 patients with neovascular AMD to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation. The primary outcome was the mean change in visual acuity at 1 year, with a non-inferiority limit of 5 letters on the eye chart.
Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 μm) than in the other groups (152 to 168 μm, P = 0.03 by analysis of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab (P>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern.
At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered according to the same schedule. Ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab administered monthly. Differences in rates of serious adverse events require further study. (Funded by the National Eye Institute; number, NCT00593450.)
PMCID: PMC3157322  PMID: 21526923
16.  Profile of ranibizumab: efficacy and safety for the treatment of wet age-related macular degeneration 
Wet age-related macular degeneration (AMD) causes severe vision loss due to the development of choroidal neovascularization (CNV). The critical role of vascular endothelial growth factor in the pathogenesis of CNV is well understood. Ranibizumab plays an inhibitory role with CNV and reduces vascular permeability by binding to vascular endothelial growth factor. Intravitreal ranibizumab reduces the risk of visual acuity (VA) loss and increases the chance of VA gain compared with no treatment or photodynamic therapy for CNV in AMD. Some high-quality research has shown that the optimal timing for ranibizumab treating wet AMD is the first 3 months. It is recommended that ranibizumab is intravitreally injected monthly in the initiation for at least 3 months. Subsequent managing of regimens should be made dependent on the VA change, fundus examination, and image of optical coherence topography. An individualized strategy or combined method with photodynamic therapy is beneficial to the active lesion in the consecutive treatment of ranibizumab for CNV, and may be a good choice in order to decrease injection times. Regarding the safety profile, ranibizumab has been well tolerated in clinical trials. The principal ocular adverse event detected in clinical trials is a low frequency of ocular inflammation. Key serious ocular adverse events occurred in <5% of ranibizumab-treated patients in large-scale clinical trials. It appears unlikely that treatment with ranibizumab increases the risk of vascular events significantly. Less frequent injections on an as-needed schedule, based on monthly monitoring may have the most optimal risk:benefit ratio.
PMCID: PMC3404592  PMID: 22911433
age-related macular degeneration; choroidal neovascularization; ranibizumab; efficacy; safety
17.  Anti-vascular endothelial growth factor for neovascular age-related macular degeneration 
Age-related macular degeneration (AMD) is the most common cause of uncorrectable severe vision loss in people aged 55 years and older in the developed world. Choroidal neovascularization (CNV) secondary to neovascular AMD accounts for most AMD-related severe vision loss. Anti-vascular endothelial growth factor (anti-VEGF) agents, injected intravitreally, aim to block the growth of abnormal blood vessels in the eye to prevent vision loss and, in some instances, improve vision.
To investigate: (1) the ocular and systemic effects of, and quality of life associated with, intravitreally injected anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) for the treatment of neovascular AMD compared with no anti-VEGF treatment; and (2) the relative effects of one anti-VEGF agent compared with another when administered in comparable dosages and regimens.
Search methods
We searched Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to March 2014), EMBASE (January 1980 to March 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to March 2014), the metaRegister of Controlled Trials (mRCT) (, ( and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) ( We used no date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 27 March 2014.
Selection criteria
We included randomized controlled trials (RCTs) that evaluated pegaptanib, ranibizumab, or bevacizumab versus each other or a control treatment (e.g., sham treatment or photodynamic therapy). All trials followed participants for at least one year.
Data collection and analysis
Two review authors independently screened records, extracted data, and assessed risks of bias. We contacted trial authors for additional data. We analyzed outcomes as risk ratios (RRs) or mean differences (MDs). We used the standard methodological procedures expected by The Cochrane Collaboration.
Main results
We included 12 RCTs including a total of 5496 participants with neovascular AMD (the number of participants per trial ranged from 28 to 1208). One trial compared pegaptanib, three trials ranibizumab, and two trials bevacizumab versus controls; six trials compared bevacizumab with ranibizumab. Four trials were conducted by pharmaceutical companies; none of the eight studies which evaluated bevacizumab were funded by pharmaceutical companies. The trials were conducted at various centers across five continents (North and South America, Europe, Asia and Australia). The overall quality of the evidence was very good, with most trials having an overall low risk of bias.
When compared with control treatments, participants who received any of the three anti-VEGF agents were more likely to have gained 15 letters or more of visual acuity, lost fewer than 15 letters of visual acuity, and had vision 20/200 or better after one year of follow up. Visual acuity outcomes after bevacizumab and ranibizumab were similar when the same regimens were compared in the same RCTs, despite the substantially lower cost for bevacizumab compared with ranibizumab. No trial directly compared pegaptanib with other anti-VEGF agents; however, when compared with controls, ranibizumab or bevacizumab yielded larger improvements in visual acuity outcomes than pegaptanib.
Participants treated with anti-VEGFs showed improvements in morphologic outcomes (e.g., size of CNV or central retinal thickness) compared with participants not treated with anti-VEGF agents. There was less reduction in central retinal thickness among bevacizumab-treated participants than among ranibizumab-treated participants after one year (MD −13.97 μm; 95% confidence interval (CI) −26.52 to −1.41); however, this difference is within the range of measurement error and we did not interpret it as being clinically meaningful.
Ocular inflammation and increased intraocular pressure after intravitreal injection were the most frequently reported serious ocular adverse events. Endophthalmitis was reported in fewer than 1% of anti-VEGF treated participants; no cases were reported in control groups. The occurrence of serious systemic adverse events was comparable across anti-VEGF-treated groups and control groups; however, the numbers of events and trial participants may have been insufficient to detect a meaningful difference between groups. Data for visual function, quality of life, and economic outcomes were sparsely measured and reported.
Authors’ conclusions
The results of this review indicate the effectiveness of anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) in terms of maintaining visual acuity; ranibizumab and bevacizumab were also shown to improve visual acuity. The information available on the adverse effects of each medication do not suggest a higher incidence of potentially vision-threatening complications with intravitreal injection compared with control interventions; however, clinical trial sample sizes may not have been sufficient to detect rare safety outcomes. Research evaluating variable dosing regimens with anti-VEGF agents, effects of long-term use, combination therapies (e.g., anti-VEGF treatment plus photodynamic therapy), and other methods of delivering the agents should be incorporated into future Cochrane reviews.
PMCID: PMC4270425  PMID: 25170575
Angiogenesis Inhibitors [*therapeutic use]; Antibodies, Monoclonal [therapeutic use]; Antibodies, Monoclonal, Humanized, Aptamers, Nucleotide [therapeutic use]; Choroidal Neovascularization; Macular Degeneration [*drug therapy]; Porphyrins [therapeutic use]; Randomized Controlled Trials as Topic; Vascular Endothelial Growth Factor A [*antagonists & inhibitors]; Aged; Humans; Middle Aged
18.  Involvement of genetic factors in the response to a variable-dosing ranibizumab treatment regimen for age-related macular degeneration 
Molecular Vision  2010;16:2598-2604.
To determine whether gene polymorphisms of the major genetic risk factor for age-related macular susceptibility 2 (ARMS2 A69S) and the complement factor H Y402H influence the response to a variable-dosing treatment regimen with ranibizumab for age-related macular degeneration.
This prospective cohort study included 90 patients (90 eyes) with exudative age related macular degeneration (AMD) treated with ranibizumab. Patients underwent a 1-year treatment as in the Study of Ranibizumab in Patients with Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration (Mitchell et al.). Injections were administered monthly when a patient lost five letters on the Early Treatment Diabetic Retinopathy Study chart or gained 100 μm in central subfield retinal thickness (CSRT). Genotypes (rs10490924 and rs1061170) were analyzed using gene sequence analysis. Best-corrected visual acuity (BCVA) and CSRT values were compared between ARMS2 and complement factor H genotypes. Multiple regression analysis was used to assess the statistical significance.
Mean increase in visual acuity was 4.44±8.12 letters with a 103.63±94.7 µm decrease in CSRT. BCVA improvement was statistically significant in all genotype groups except in homozygous 69S in the AMRS2 gene. CSRT and BCVA changes were correlated (r=0.2521; 95% CI: 0.04746–0.4364, p=0.0165). Multiple regression analysis revealed a significant impact of 69S (p=0.015) on the change in BCVA.
Visual acuity did not improve during the study in patients homozygous for ARMS2 69S, despite a decrease in CSRT. Further investigation is needed to confirm our findings and understand the mechanisms involved.
PMCID: PMC3000236  PMID: 21151600
19.  Current Smoking Is Associated with a Poor Visual Acuity Improvement after Intravitreal Ranibizumab Therapy in Patients with Exudative Age-Related Macular Degeneration 
Journal of Korean Medical Science  2013;28(5):769-774.
In this study, the risk factors that may influence visual improvement after intravitreal ranibizumab (IVR) treatment for exudative age-related macular degeneration (AMD) were examined. From 2008 to 2012, 420 patients (448 eyes) with exudative AMD were prospectively registered at Seoul National University Hospital. From this group of patients, 125 eyes were included in this study. All patients were treated with 3 consecutive IVR injections. The visual acuity (VA) was evaluated at baseline and 1 month after the third ranibizumab injection. To evaluate the risk factors associated with VA improvement after IVR, patient demographic data and systemic risk factors were analyzed. Patients were divided into a poor VA improvement group and a good VA improvement group, with reference to the median visual improvement in all eyes. Among 125 eyes, 66 eyes (52.8%) were included in the responder group and 59 eyes (47.2%) in the non-responder group. The median VA improvement after 3 monthly ranibizumab injections was -0.05 logMAR. Multivariate analyses revealed that current smoking (adjusted OR, 7.540; 95% CI, 1.732-32.823) was independently associated with poor VA improvement after IVR treatment for exudative AMD. In conclusion, cigarette smoking is an independent risk factor for lower VA gains with IVR treatment for exudative AMD.
PMCID: PMC3653092  PMID: 23678271
Exudative Age-Related Macular Degeneration; Ranibizumab; Cigarette Smoking
20.  Comparison of visual acuity outcomes between ranibizumab and bevacizumab treatment in neovascular age-related macular degeneration 
To compare visual acuity (VA) outcomes between intravitreal injection of bevacizumab and ranibizumab in the treatment of neovascular age-related macular degeneration (AMD).
We conducted a consecutive, retrospective case series study in patients with newly diagnosed all type choroidal neovascularization (CNV) secondary to AMD who received an intravitreal injection of bevacizumab (1.25mg) or ranibizumab (0.3mg) at Lions Eye Institute, Western Australia from Mar. 2006 to May 2008. All patients received injection at baseline with additional monthly injections given at the discretion of the treating physician. Main outcome measures were changes in VA.
There were 371 consecutive patients received injection at least in one eye with at least 6 months of follow up (median of 12.0 months). Bevacizumab treatment prevented 221 out of 278 (79.5%) patients from losing < 15 letters in VA compared with 79 out of 93 (84.9%) of ranibizumab treated patients (P=0.25). While 68 (24.5%) of bevacizumab treated patients gained ≥15 letters of VA compared with 24 (25.8%) of ranibizumab treated patients (P=0.79). 75.3% and 66.2% patients benefited from ranibizumab and bevacizumab respectively with final VA better than 6/60 (P=0.10). Multivariate analysis showed that pre-treatment VA was negatively associated with benefit outcome. Assignment of injection was not associated with VA outcome of benefit after adjusting the covariate (P=0.857).
There are no difference in treatment efficacy in terms of VA between bevacizumab and ranibizumab in routine clinical condition.
PMCID: PMC3340678  PMID: 22553617
age-related macular degeneration; anti-VEGF; bevacizumab; ranibizumab; choroidal neovascularization
21.  Comparative role of intravitreal ranibizumab versus bevacizumab in choroidal neovascular membrane in age-related macular degeneration 
Indian Journal of Ophthalmology  2011;59(3):191-196.
Ranibizumab and bevacizumab are used widely for treating patients with choroidal neovascular membrane (CNVM) secondary to age-related macular degeneration (AMD).
To determine and compare the efficacy and safety of intravitreal ranibizumab and bevacizumab in treatment of CNVM due to AMD.
Settings and Design:
Prospective comparative case series carried out in an eye institute and eye department of a hospital in Kolkata, India.
Materials and Methods:
One hundred and four eyes with CNVM due to AMD were randomized into two groups. Group A (n=54; 24 occult) received monthly intravitreal ranibizumab injections (0.5 mg in 0.05 ml) and Group B (n=50; 22 occult) received monthly bevacizumab injections (1.25 mg in 0.05 ml) for 3 consecutive months and then as per study criteria. Data analysis done using SPSS software. P-value of <0.05 was considered statistically significant.
The mean best corrected visual acuity (BCVA) in the ranibizumab group increased from 58.19 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at baseline to 64 ETDRS letters at month 3 (P<0.001). In bevacizumab group mean BCVA increased from 56.80 to 61.72 ETDRS letters at month 3 (P<0.001). At the end of 18 months, there was no statistically significant difference between groups A and B with respect to change in BCVA (P=0.563) or central macular thickness (CMT; P=0.281), as measured by optical coherence tomography (Stratus OCT 3000). No significant sight-threatening complications developed.
Ranibizumab and bevacizumab are equally safe and efficacious in treating CNVM due to AMD.
PMCID: PMC3120237  PMID: 21586838
Ranibizumab; bevacizumab; choroidal neovascular membrane; age-related macular degeneration; intravitreal injection; central macular thickness; best corrected visual acuity
22.  Pilot study to evaLuate the role of high-dose rAnibizumab 2.0 mg in the management of neovascular age-related macular degeneration in patients with perSistent/recurrenT macular fluid <30 days following treatment with intravitreal anti-VEGF therapy (the LAST Study) 
Eye  2012;26(9):1181-1187.
To determine the efficacy of intravitreal ranibizumab 2.0 mg in patients with recalcitrant neovascular age-related macular degeneration (AMD).
This single-masked, randomized, prospective, pilot study enrolled patients with subfoveal neovascular AMD. All study eyes had persistent subretinal (SRF) or intraretinal fluid (IRF) on spectral-domain optical coherence tomography (SD-OCT) <30 days following at least 6 monthly intravitreal injections of ranibizumab or bevacizumab. Patients were randomized 2 : 1 to receive either ranibizumab 2.0 or 0.5 mg. Following three-loading treatments 4-weeks apart, both groups were treated using a ‘treat and extend' regimen guided by eye-tracked SD-OCT through month 12. The primary end point was the mean change in best-corrected visual acuity (BCVA) at month 6.
Nine eyes of 9 patients (mean age±SD, 82.0±5.8 years) were enrolled. Seven eyes received ranibizumab 2.0 mg and two eyes received 0.5 mg. Owing to the small number of patients enrolled, no statistical comparison could be made between the two dosages. At month 6, the mean improvement in BCVA was +6.1±3.7 (W=0, P<0.001) ETDRS letters and +2.0 ETDRS letters in the 2.0 and 0.5 mg groups, respectively. In the 2.0 mg group, there was a statistically significant decline in central foveal thickness, SRF and maximum pigment epithelial detachment height at 6 months compared with baseline. No adverse events were reported in either group.
Ranibizumab 2.0 mg has the potential to maintain or improve BCVA in some patients with persistent or recurrent SRF or IRF secondary to neovascular AMD despite prior monthly intravitreal anti-vascular endothelial growth factor therapy with the standard dose.
PMCID: PMC3443842  PMID: 22878451
age-related macular degeneration; choroidal neovascularisation; vascular endothelial growth factor; ranibizumab
23.  Antiangiogenic therapy with anti-vascular endothelial growth factor modalities for neovascular age-related macular degeneration 
Age-related macular degeneration (AMD) is a common cause of severe vision loss in people 55 years and older.
The objective of this review was to investigate the effects of anti-VEGF (vascular endothelial growth factor) modalities for treating neovascular AMD.
Search strategy
We searched CENTRAL, MEDLINE, EMBASE and LILACS. We handsearched ARVO abstracts for 2006, 2007 for ongoing trials.
Selection criteria
We included randomized controlled trials (RCTs).
Data collection and analysis
Two review authors independently extracted data. We contacted trial authors for additional data. We summarized outcomes as relative risks (RR), number needed to treat (NNT) and weighted mean differences.
Main results
We included five RCTs of good methodological quality. All five trials were conducted by pharmaceutical companies. An intention-to-treat analysis using the last observation carried forward method was done in most trials.
Two trials compared pegaptanib versus sham. One trial compared ranibizumab versus sham, another compared ranibizumab/sham verteporfin PDT versus verteporfin PDT/sham ranibizumab, and the final trial compared ranibizumab plus verteporfin PDT versus verteporfin PDT alone.
Fewer patients treated with pegaptanib lost 15 or more letters of visual acuity at one year follow-up compared to sham (pooled relative risk (RR) 0.71; 95% confidence interval (CI) 0.61 to 0.84). The NNT was 6.67 (95% CI 4.35 to 14.28) for 0.3 mg pegaptanib, 6.25 (95% CI 4.17 to 12.5) for 1 mg pegaptanib and 14.28 (95% CI 6.67 to 100) for 3 mg pegaptanib. In a trial of ranibizumab versus sham, RR for loss of 15 or more letters visual acuity at one year was 0.14 (95% CI 0.1 to 0.22) in favour of ranibizumab. The NNT was 3.13 (95% CI 2.56 to 3.84) for 0.3 mg ranibizumab and 3.13 (95% CI 2.56 to 3.84) for 0.5 mg ranibizumab. In a trial of ranibizumab versus verteporfin PDT, RR for loss of 15 or more letters at one year was 0.13 (95% CI 0.07 to 0.23) favouring ranibizumab. The NNT was 3.33 (95% CI 2.56 to 4.76) for 0.3 mg ranibizumab and 3.12 (95% CI 2.43 to 4.17) for 0.5 mg ranibizumab. In another trial of combined ranibizumab plus verteporfin PDT versus verteporfin PDT, RR for loss of 15 or more letters at one year favoured combined therapy (RR 0.3 (95% CI 0.15 to 0.60). The NNT was 4.35 (95% CI 2.78 to 11.11).
Pooled RR for gain of 15 or more letters visual acuity at one year was 5.81 (95% CI 3.29 to 10.26) for ranibizumab versus sham, 6.79 (95% CI 3.41 to 13.54) for ranibizumab/sham verteporfin PDT versus verteporfin PDT/sham ranibizumab, and 4.44 (95% CI 1.40 to 14.08) for ranibizumab plus verteporfin PDT versus verteporfin PDT.
Frequency of endophthalmitis in included studies was between 0.7% to 4.7% with ranibizumab and 1.3% with pegaptanib. Improvement in vision-specific quality of life was reported for both treatments.
Authors' conclusions
Pegaptanib and ranibizumab reduce the risk of visual acuity loss in patients with neovascular AMD. Ranibizumab causes gains in visual acuity in many eyes. Quality of life and cost will be important for treatment decisions. Other agents blocking VEGF are being tested in ongoing trials.
PMCID: PMC4267250  PMID: 18425911
Angiogenesis Inhibitors [*therapeutic use]; Antibodies; Monoclonal [therapeutic use]; Aptamers; Nucleotide [therapeutic use]; Choroidal Neovascularization; Macular Degeneration [*drug therapy]; Porphyrins [therapeutic use]; Randomized Controlled Trials as Topic; Vascular Endothelial Growth Factor A [*antagonists & inhibitors]; Aged; Humans; Middle Aged
24.  A pharmacogenetics study to predict outcome in patients receiving anti-VEGF therapy in age related macular degeneration 
To ascertain whether single nucleotide polymorphisms (SNPs) in the Vascular Endothelial Growth factor (VEGFA), Complement Factor H (CFH), and LOC387715 genes could predict outcome to anti-VEGF therapy for patients with age related macular degeneration (AMD).
Patients with “wet” AMD were identified by chart review. Baseline optical coherence tomography (OCT) and visual acuity (VA) data, and at least 6 months of clinical follow up after 3 initial monthly injections of bevacizumab or ranibizumab were required for inclusion. Based on OCT and VA, patients were categorized into two possible clinical outcomes: (a) responders and (b) non-responders. DNA was extracted from saliva and genotyped for candidate SNPs in the VEGFA, LOC387715, and CFH genes. Clinical outcomes were statistically compared to patient genotypes.
101 patients were recruited, and one eye from each patient was included in the analysis. 97% of samples were successfully genotyped for all SNPs. We found a statistically significant association between the LOC387715 A69S TT genotype and outcome based on OCT.
Genetic variation may be associated with outcome in patients receiving anti-VEGF therapy.
PMCID: PMC3797648  PMID: 24143065
age related macular degeneration; ARMS2; bevacizumab; complement factor H (CFH); LOC387715; ranibizumab; single nucleotide polymorphisms; vascular endothelial growth factor
25.  Visual outcome of intravitreal ranibizumab for exudative age-related macular degeneration: timing and prognosis 
To describe 1-year clinical results of intravitreal ranibizumab treatment in patients with choroidal neovascularization secondary to exudative age-related macular degeneration (AMD) and to evaluate whether early treatment is a predictive value for prognosis of the disease.
Materials and methods
Clinical records were retrospectively reviewed of 104 eyes that underwent intravitreal ranibizumab therapy for exudative AMD. Patients were divided into two groups according to their symptom duration: group 1, <1 month; and group 2, 1–3 months. After three monthly injections, patients were examined monthly, and subsequent injections were performed as needed.
There were 43 female (48.9%) and 45 males (51.1%). The follow-up time was 13.7±1.9 (12–19) months. The mean logarithm of minimum angle of resolution best-corrected visual acuity (BCVA) improved significantly, from 0.45±0.639 at baseline to 0.08±0.267 at 12 months in group 1, and from 1.06±0.687 at baseline to 0.75±0.563 at 12 months in group 2. The increase in BCVA was statistically significant in group 1 (P=0.009). The mean central retinal thickness (CRT) decreased significantly, from 355.13±119.93 μm at baseline to 250.85±45.48 μm at 12 months in group 1, and from 371.88±91.047 μm at baseline to 268.61±53.51 μm at 12 months in group 2. The decrease in CRT was statistically significant in group 1 (P=0.001).
Intravitreal ranibizumab therapy was effective in significantly increasing mean BVCA and reducing CRT. Shorter duration of AMD, as measured by the subjective duration of visual symptoms, is associated with better visual outcome after treatment.
PMCID: PMC3894137  PMID: 24453484
age-related macular degeneration (AMD); optical coherence tomography (OCT); ranibizumab; visual acuity

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