|Year : 2013 | Volume
| Issue : 3 | Page : 138-145
Ranibizumab versus bevacizumab in choroidal neovascular membrane: Is it worth it?
Department of Ophthalmology, Mansourah University
|Date of Submission||10-Oct-2013|
|Date of Acceptance||10-Oct-2013|
|Date of Web Publication||28-Feb-2014|
Department of Ophthalmology,Mansourah University
Source of Support: None, Conflict of Interest: None
The aim of this study was to compare the short-term outcomes of administration of intravitreal ranibizumab (IVR) and intravitreal bevacizumab (IVB) in the treatment of neovascular age-related macular degeneration (AMD).
This study is a clinical interventional randomized comparative study.
Patients and methods
This randomized clinical trial was performed on 24 eyes of 24 patients with subfoveal and juxtafoveal choroidal neovascularization secondary to AMD. The eyes were randomly assigned to receive 0.5 mg IVR (group 1; 12 eyes) or 1.25 mg IVB (group 2; (12 eyes). Best-corrected visual acuity (BCVA) was assessed, optical coherence tomography was carried out at baseline and repeated at all postoperative follow-up intervals (1 week and 1, 3, and 6 months), and fluorescein angiography was performed at baseline and repeated 1 month after treatment.
In group 1, the mean age was 62.42 ± 6.75 years (range 51-70 years) and seven of the patients were male (58.33%). In group 2, the mean age was 62.083 ± 7.96 years (range 50-75 years) and four of the patients were male (33.33%). At the sixth month postoperatively, BCVA logMAR significantly improved from 1.01 ± 0.26 (range 1.5-0.7) to 0.82 ± 0.18 (range 1.2-0.5; P = 0.001) in group 1 and from 0.98 ± 0.279 (range 1.4-0.5) to 0.81 ± 0124 (range 1.0-0.7; P = 0.004) in group 2. At 6 months postoperatively, the mean ± SD central macular thickness reduced from 363.33 ± 27.16 μm at baseline (range 319-405 μm) to 291.67 ± 25.79 μm (range 243-335 μm) in group 1 (P = 0.00), whereas in group 2, the mean ± SD central macular thickness moderately reduced from 362.5 ± 20.26 μm at baseline (range 339-400 μm) to 294.17 ± 29.62 μm (range 257-350 μm) at 6 months postoperatively (P = 0.00). There were no significant systemic or ophthalmological adverse effects in either group.
Both ranibizumab and bevacizumab are equally safe and effective treatment options as intravitreal injections in the treatment of CNVM due to AMD.
Keywords: Ranibizumab, Bevacizumab, Choroidal Neovascular Membrane
|How to cite this article:|
Khattab A. Ranibizumab versus bevacizumab in choroidal neovascular membrane: Is it worth it?. J Egypt Ophthalmol Soc 2013;106:138-45
| Introduction|| |
Age-related macular degeneration (AMD) is a leading cause of severe and irreversible vision loss among people 50 years or older . The neovascular form of the disease usually cause severe vision loss and is characterized by the abnormal growth of new blood vessels under or within the macula, which is the central portion of the retina responsible for high-resolution vision ,,. The pathogenesis of neovascular AMD is complex ,; choroidal neovascularization (CNV) may be initiated by a number of events, such as reduction in choriocapillaris blood flow, accumulation of lipid metabolic byproducts, oxidative stress, and alterations in Bruch's membrane ,,,,. In response to metabolic distress, the retinal pigment epithelium and the retina produce factors, vascular endothelial growth factor (VEGF) in particular, that act through a variety of mechanisms, causing CNV. VEGF, a central mediator of angiogenesis, seems to play a major role in the development of CNV in AMD. Accordingly, the development of antiangiogenic therapies has been a major goal in AMD research ,. Thus, anti-VEGF agents have recently been used to treat CNV secondary to AMD ,,.
Ranibizumab (Lucentis; Genentech/Novartis) is an anti-VEGF humanized recombinant monoclonal antibody fragment recently developed for intraocular use and designed to recognize all five human isoforms of VEGF. It is a small molecule that can theoretically penetrate all retinal layers better than a full-length antibody such as bevacizumab and inhibit VEGF-A, thereby decreasing vascular permeability and blocking angiogenesis ,,,. Ranibizumab was licensed as an intravitreal treatment for exudative AMD by the Food and Drug Administration (FDA) and for the treatment of all angiographic subtypes of subfoveal neovascular AMD by the European Union in the year 2006 ,. Ranibizumab is delivered by monthly intravitreal injections. Ranibizumab, in clinical trials, has been shown to stop and, in many cases, reverse at least some vision loss in most people with advanced AMD ,,. Improvement in visual acuity after treatment with ranibizumab as observed on optical coherence tomography (OCT) was associated with a reduction in intraretinal and subretinal fluid, and inhibition of neovascular growth and leakage in a range of lesion types was demonstrated on fluorescein angiography. These positive findings clearly make ranibizumab by far the most effective FDA-approved treatment currently available for more damaging forms of AMD. The most common adverse effects of intravitreal ranibizumab include conjunctival hemorrhage, eye pain, and vitreous floaters ,,.
Bevacizumab (Avastin; Genentech Inc.) is a humanized monoclonal antibody to VEGF designed for intravenous administration; it was approved for the treatment of colorectal cancer in the year of 2004 . It is derived from the same murine anti-VEGF antibody as ranibizumab. It has two antigen-binding domains and a longer half life than ranibizumab of about 17-21 days . The promising results obtained with bevacizumab have raised the expectations of retina specialists, as well as of patients ,. Although bevacizumab has a license for the treatment of colorectal cancer it is not licensed for the treatment of AMD and is therefore available for use as an off-label treatment for age-related and myopic choroidal neovascular membranes ,,. Following the publication of highly encouraging data, many investigators worldwide are exploring the use of intravitreal bevacizumab, with several reports on short-term safety and efficacy available in the literature ,,,. In addition, experimental and electrophysiological testing in animals and humans have demonstrated the absence of toxicity to the retina ,. Despite the promising results reported, administration of intravitreal bevacizumab cannot be formally recommended until results of a randomized clinical trial are available ,.
Both Lucentis and Avastin are produced by the same company - Genentech, based in San Francisco. The two drugs are almost equal in their effectiveness, but their safety and long-term effects will be studied further ,,,. It is argued that bevacizumab, which is closely related to ranibizumab, is a highly effective and far cheaper alternative; a single bevacizumab vial can be fractionated into multiple unit doses when administered as an intraocular injection, which is useful for lower-income individuals with advanced AMD ,. This cost difference has led to widespread use of bevacizumab as an alternative; many eye doctors have been using Avastin as an off-label treatment . In fact, ranibizumab should be at least 2.5-fold more efficacious than bevacizumab for it to be cost-effective ,. Thus, there is a very urgent need for large multicentre randomized controlled prospective studies comparing these two drugs with respect to their efficacies and safety profile ,,,,,,,,,,,,.
The aim of this study was to compare efficacy and safety of both ranibizumab and bevacizumab in the treatment of age-related choroidal neovascular membrane in order to estimate the cost-to-benefit ratio.
| Patients and methods|| |
This clinical interventional randomized comparative study included 24 patients (24 eyes) diagnosed with age-related choroidal neovascular membrane. They were selected from patients attending the ophthalmology outpatient clinic of Al Bahar Eye Center, Ibn Sinai Hospital of Kuwait Ministry of Health, which is the outpatient tertiary care referral center for vitreoretinal care, in the period between July 2009 and December 2009. The inclusion criteria were as follows: (i) patients aged more than 50 years; (ii) all cases of CNV with classic and occult lesions; (iii) patients diagnosed as having subfoveal or juxtafoveal CNV due to AMD; (iv) CNV of 5400 μm or lower in greatest linear diameter; (v) cases with active leakage pattern with presence of fluid in the macula on OCT greater than or equal to 250 μm; (vi) duration of symptoms of no longer than 12 months; and (vi) patients who declined other modalities of treatment such as laser, PDT, and ranibizumab after discussion. Exclusion criteria were as follows: (i) other serious eye diseases, including diabetic retinopathy, hypertensive retinopathy, macular dystrophy, angioid streaks, glaucoma with glaucomatous field loss, epiretinal membranes, macular hole, uveitis, or subfoveal scarring or hemorrhage; (ii) macular scarification; (iii) previous treatment for CNV in either eye; (iv) history of ocular surgery within the last 6 months; (v) one-eyed patients; (vi) the use of systemic corticosteroids or any drug that affects the macula including chloroquine, hydroxychloroquine sulfate, thioridazine, and chlorpromazine; (vii) history of cerebrovascular accident and myocardial infarction; and (viii) any mental, social, or physical condition that would affect regular follow-up. The selected patients were randomly allocated into two groups. Each group included 12 patients (12 eyes). The first group (group 1) received three consecutive intravitreal ranibizumab injections 1 month apart, whereas the second group (group 2) received three consecutive intravitreal bevacizumab injections 1 month apart. The mean age of the patients was 62.42 ± 6.75 and 62.083 ± 7.96 years in the first and second group, respectively (mean ± SD). All patients were fully informed about the experimental nature of the therapy; the off-label use of bevacizumab; the potential risks, benefits, and adverse effects; alternative treatment options; and possible treatment outcomes; they were also given a detailed explanation of the procedure, and they all signed informed consent forms. The study was approved by the hospital ethics committee. Baseline workup included evaluation of automatic objective refraction, measurement of best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, intraocular pressure (IOP) measurement, and contact lens slit-lamp biomicroscopy. The diagnosis of the choroidal neovascular membrane was made on the basis of a typical ophthalmoscopic appearance, fluorescein angiography (Imagenet; Topcon Corp., Tokyo, Japan), and spectral domain optical coherence tomography (3D OCT; Topcon Corp.). A standard protocol for intravitreal injections was followed: all procedures were carried out in the operative room (minor procedures area in the operative theater under full aseptic conditions); 0.4% topical benoxinate hydrochloride and 5% topical povidone-iodine (Betadine; Alcon Laboratories Inc., Fort Worth, Texas, USA) were applied; an eye drape and eyelid speculum were used; and postoperative topical antibiotic drops were administered. In the first group, an intravitreal injection of 0.5 mg ranibizumab (Lucentis) in 0.05 ml was administered using a 27 G needle transconjunctivally through the temporal inferior pars plana, at 3.5-4.0 mm from the limbus. In the second group, 1.25 mg bevacizumab (Avastin) in 0.05 ml was injected using a 27 G needle transconjunctivally through the temporal inferior pars plana, at 3.5-4.0 mm from the limbus. The patients were followed up for 6 h after injection to check for visual acuity, changes in IOP, and status of the optic disc. The patients were asked to return the following day for reassessment of IOP and detection of any sign of intraocular inflammation or infection. Whenever IOP exceeded 24 mmHg, patients were given topical medication to reduce the pressure. This injection was repeated every month for three consecutive months in both ranibizumab and bevacizumab groups. Follow-up included re-examinations at ∼1 week and 1, 3, and 6 months. Main outcomes measures of treatment were changes in BCVA and central macular thickness (CMT) on OCT.
BCVA was measured on the basis of Snellen's table and transformed into logMAR values for statistical purposes. Repeated measures analysis of variance was carried out to analyze the changes in BCVA logMAR and CMT from baseline to final visit. When the P-value from analysis of variance was significant, pairwise comparisons were used to compare the mean BCVA levels and CMT measurements at different follow-up visits. The independent samples t-test was used to evaluate associations between the mean changes in BCVA logMAR and CMT scores at baseline and all postoperative interval characteristics. SPSS version 17.0 statistical software was used for data analysis (SPSS Inc., Chicago, Illinois, USA). P less than 0.05 was considered statistically significant.
| Results|| |
Twenty-four eyes of 24 patients who met the inclusion criteria were included in this study. Twelve patients (12 eyes) were assigned to the ranibizumab therapy group and 12 patients (12 eyes) were assigned to the bevacizumab therapy group. No patient in either group had undergone previous therapy. All patients completed the 6 months follow-up period of the study and were able to adhere to scheduled appointments with no more than a 7-day delay. The first group included seven men (58.33%) and five women (41.67%); the mean ( ± SD) age was 62.42 ± 6.75 years (range 51-70 years). The second group included four men (33.33%) and eight women (66.67%); the mean age was 62.083 ± 7.96 years (range 50-75 years). Patient demographic features at baseline were comparable between the study groups [Table 1].
Ocular features at baseline were comparable between the studied groups as regards the preoperative mean BCVA logMAR, as well as the preoperative mean CMT. There was minimal difference in the mean BCVA logMAR, as well as CMT, between both groups, and this difference was statistically insignificant (P = 0.822 and 0.933, respectively; [Figure 1] and [Figure 2]).
In group 1, the mean ± SD BCVA logMAR at baseline was 1.01 ± 0.26 (range 1.5-0.7); it minimally improved to 0.98 ± 0.314 (range 1.5-0.5) at 1 week postoperatively, and this increase was statistically insignificant (P = 0.504). At 1 month postoperatively, BCVA logMAR markedly improved to 0.86 ± 0.257 (range 1.4-0.5), and this improvement was statistically highly significant (P = 0.001). BCVA continued to improve at the third month postoperatively (P = 0.00), at which the mean was 0.83 ± 0.176 (range 1.2-0.5). At the sixth month of follow-up, the mean BCVA continued to improve, compared with that during the first and third month, with a mean of 0.82 ± 0.18 (range 1.2-0.5); this was statistically highly significant compared with the preoperative values (P = 0.001).
In group 2, the mean ± SD baseline BCVA logMAR was 0.98 ± 0.279 (range 1.4-0.5), which slightly decrease at 1 week of follow-up to a mean of 1.0 ± 0.259 (range 1.4-0.5), and this decrease was statistically insignificant (P = 0.795). At 1 month after injection, moderate improvement in the mean BCVA logMAR was observed [0.91 ± 0.21, range 1.2-0.5], and this improvement was statistically moderately significant (P = 0.044) when compared with the mean preoperative BCVA. This improvement continued until the end of the follow-up period; at the third month postoperatively, the mean was 0.82 ± 014 (range 1.0-0.7; P = 0.002), whereas the mean at the sixth month postoperatively was 0.81 ± 0124 (range 1.0-0.7; P = 0.004), and this improvement was statistically highly significant.
The change in the mean BCVA logMAR between the ranibizumab and bevacizumab groups was compared [Figure 1], and significance was tested using the independent samples t-test. The P-values at 1 week and 1, 3, and 6 months were 0.822, 0.834, 0.608, and 0.899, respectively. Thus, there was no statistically significant difference in the change in BCVA logMAR in the two groups at all preoperative and postoperative intervals.
Central macular thickness outcomes
In group 1, the mean ± SD CMT at baseline was 363.33 ± 27.16 μm (range 319-405 μm). At 1 week postoperatively, the CMT significantly reduced to 333.33 ± 28.93 μm (range 277-396 μm), and this reduction was highly statistically significant (P = 0.000). At 1 month after injection, the reduction in CMT continued to 316.42 ± 22.56 μm (range 282-369 μm), and this was statistically highly significant when compared with the preoperative values (P = 0.000). Similarly, at the third and sixth month postoperatively, there was further reduction in the CMT values compared with the preoperative values and the postoperative values at the first week and first month, respectively; the mean ± SD was 297.25 ± 27.28 μm (range 257-355 μm) and 291.67 ± 25.79 μm (range 243-335 μm) at the third and sixth month, respectively, and this reduction was statistically highly significant when compared with the preoperative values (P = 0.000; [Figure 2]).
In group 2, the mean ± SD CMT at baseline was 362.5 ± 20.26 μm (range 339-400 μm). At 1 week postoperatively, the CMT reduced to 337.75 ± 29.5 μm (range 290-390 μm), and this reduction was highly statistically significant (P = 0.000). At 1 month postoperatively, the mean ± SD CMT was 314.42 ± 26.04 μm (range 283-370 μm), and this was also statistically highly significant when compared with the preoperative values (P = 0.000). At the third month postoperatively, the CMT further reduced to 303.42 ± 30.86 μm (range 271-365 μm; P = 0.000). In addition, at the sixth month postoperatively, there was slight decrease in the mean CMT value compared with that during the third month postoperatively; the mean ± SD CMT was 294.17 ± 29.62 μm (range 257-350 μm), and this reduction in the mean value compared with the preoperative values was statistically highly significant (P = 0.000; [Figure 2]).
When the mean change in CMT between the ranibizumab and bevacizumab groups was compared, no statistically significant difference was detected between the two groups at 1 week and 1, 3, and 6 months postoperatively (P = 0.715, 0.842, 0.612, and P = 0.779, respectively).
There were no significant systemic complications or ocular side effects such as increased IOP, endophthalmitis, traumatic lens injury, cataract, or retinal detachment in any of the eyes in both the studied groups, with the exception of varying degrees of subconjunctival hemorrhage in a few cases in both groups.
| Discussion|| |
VEGF-A is a protein that is believed to be the main form of VEGF involved in angiogenesis (the formation of new blood vessels), as well as in vascular permeability (the ability of blood vessels to allow passage of fluids and molecules) in the wet form of macular degeneration ,,.
Landmark studies have shown that the use of the VEGF-specific monoclonal antibodies, bevacizumab and ranibizumab, is currently the best treatment for patients with AMD and subfoveal CNV . Both bevacizumab and ranibizumab are semisynthetic anti-VEGF antibodies that inhibit the growth of new blood vessels and can potentially cause regression of existing vessels ,,. Despite both molecules having the same mode of action, there are distinct and potentially important differences between them . Ranibizumab was specifically developed for ocular use and intravitreal administration, whereas bevacizumab was developed for intravenous administration. Bevacizumab is a full-length antibody derived from the same murine monoclonal antibody precursor as ranibizumab, a humanized antibody fragment .
Bevacizumab has become widely used in the recent years because it costs considerably lesser than ranibizumab when administered as an intraocular injection, because of fractionation of a single bevacizumab vial into multiple unit doses. Given the marked price difference between intravitreal doses of the two molecules and an assumption of noninferiority, important data need to be generated from many studies to compare their efficacy and safety profiles .
This study aimed to provide results of a randomized clinical trial conducted over 6 months comparing bevacizumab with the current gold standard ranibizumab. The trial included 24 participants. Early results of this trial suggest that, at 6 months, visual outcomes of bevacizumab compared with ranibizumab fail to show a statistically significant difference between the two groups [Figure 1]. However, the early results at the first week and first month postoperatively were slightly in favor of ranibizumab, but still showed a statistically insignificant difference. This can be attributed to the fact that ranibizumab has a smaller molecular size and may be absorbed faster, leading to an earlier response. At the third and sixth month postoperatively, there was a slight difference in BCVA in favor of bevacizumab; this difference was also statistically insignificant. This finding is similar to that of Fung et al.  and can probably be explained by the fact that bevacizumab is a full-length molecule with a longer half life as compared with the fragmented molecule, ranibizumab, which has a shorter half life.
The results of this small series on CNV in patients with AMD are almost similar to the visual results of the large MARINA and ANCHOR trials on CNV. Safety and efficacy of intravitreal ranibizumab in neovascular AMD has been well elaborated in the ANCHOR  and MARINA  trials. The ANCHOR study showed that 94.3 and 96.4% of patients receiving 0.3 and 0.5 mg ranibizumab, respectively, lost fewer than 15 letters (<3 lines) at 12 months compared with baseline. The MARINA study showed that 94.5 and 94.6% of patients receiving 0.3 and 0.5 mg ranibizumab, respectively, lost fewer than 15 letters (<3 lines) at 12 months compared with baseline.
The efficacy of ranibizumab and bevacizumab has been demonstrated by Rosenfeld et al.  and Avery et al. . The study conducted by Avery and colleagues showed that at 1 week and 1, 2, and 3 months postoperatively, the mean retinal thickness of central 1 mm was decreased by 61, 92, 89, and 67 μm, respectively (P < 0.0001 for 1 week and 1 and 2 months, and P < 0.01 for 3 months). This is in accordance with the results of the current study as both bevacizumab and ranibizumab substantially and immediately reduced the amount of fluid in or under the retina [Figure 2], as indicated by the CMT 1 week postoperatively when compared with the preoperative values. This reduction of CMT continued throughout the follow-up period and was statistically highly significant ( P ≤ 0.000).
With a limited statistical power to detect important systemic adverse events, no significant differences between the two drugs in rates of death, arteriothrombotic events, or venous thrombotic events were found; these findings are consistent with the results of a study on Medicare claims involving more than 145 000 treated patients . In this present study, no significant ophthalmological adverse effects were reported, with varying degrees of subconjunctival hemorrhage being the most common adverse effect in both groups. No patient showed an increase in IOP above 22 mmHg or significant ocular inflammation. These observations are in line with the observations of Fung and colleagues ,. There were no reported cases of endophthalmitis in the ranibizumab group in the PIER study and this is in accordance with the findings of our study . According to the Fung et al.  the incidence of endophthalmitis after using intravitreal injections of bevacizumab was 0.01%, and this may be due to the large number of patients in their study compared with the small number of patients in this study. Lens injury or retinal detachment was not observed in any patient in this study.
There are some studies comparing the efficacies of ranibizumab and bevacizumab. Landa and colleagues , in their retrospective reviews concluded that there is no significant difference in the efficacies of ranibizumab and bevacizumab. Fong et al.  in a comparative retrospective case series concluded that both ranibizumab and bevacizumab groups showed similar improvement and stability of vision over time. Subramanian et al.  in their prospective randomized double-blind single-center study over 6 months concluded that visual outcomes of bevacizumab in wet AMD were not different from those of ranibizumab. Their study had a total of 20 patients. However, Chang et al.  in their retrospective comparative study concluded that short-term effectiveness of ranibizumab treatment, as measured by incremental improvement in OCT parameters, was significantly greater than that of bevacizumab treatment.
This study, a prospective randomized trial, was conducted at the Al Bahar Eye Center, Kuwait, and included 24 patients; the follow-up period was 6 months. Parameters studied included both change in BCVA and CMT and the adverse effects of the two drugs. In this study, no statistically significant difference was found in terms of change in BCVA or CMT between the ranibizumab and bevacizumab groups at 1, 3, and 6 months postoperatively. Both were found to be equally efficacious with regard to improving BCVA (functional improvement) or CMT (structural improvement). Hence, as there is no statistically significant difference in the efficacy and safety of ranibizumab and bevacizumab and both can be used equally as intravitreal injections for treatment of CNVM due to wet AMD.
One of the many factors that contribute to selection of a drug for a patient is cost. A single dose of ranibizumab costs 40 times as much as a single dose of bevacizumab. Hence, ranibizumab is not cost-effective compared with bevacizumab at the current prices unless it is at least 2.5 times more efficacious. However, in observational studies bevacizumab and ranibizumab appear to have similar efficacy. This cost differential has important economic implications when extrapolated to the very large number of patients who are treated for neovascular AMD, particularly when one of the suggested regimens is monthly injection of the drug. Considering all of the evidence now available, it can be concluded that ranibizumab and bevacizumab confer equivalent visual function benefits, but bevacizumab is substantially less expensive. Continuous treatment with ranibizumab results in statistically insignificant and trivially better visual function and morphologic outcomes. The safety profiles of the two drugs are similar and do not support an increased risk of arteriothrombotic events with bevacizumab. Ownership of the two drugs by a single company unwilling to license the cheaper one indicates policy limitations. The separation of licensing (on the basis of safety and efficacy) from cost effectiveness means that the company can avoid assessment of the latter by refusing to license. Although use of an unlicensed drug is not illegal, prescribers may feel pressured to use the more expensive licensed alternative. Even if a clinical trial showed the two drugs to be equivalent, it is not clear how bevacizumab could be authorized for use given the refusal by its owner to license it.
The strengths of this study are in its methodology. The prospective, randomized nature of this study helps minimize patient and investigator bias. Limitations are present and include a small sample size and a relatively short follow-up period.
| Conclusion|| |
It can be concluded that both ranibizumab and bevacizumab are safe and efficacious treatment options as intravitreal injections for the treatment of CNVM due to AMD and that the two do not have statistically significant disparity between them in terms of improving BCVA and CMT. As this study conveys results from a small number of patients, further studies with larger sample sizes are needed to establish statistical significance.
| Acknowledgements|| |
Conflicts of interest
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[Figure 1], [Figure 2]