Aim: The aim of the study was to examine the 1-year results of intravitreal bevacizumab for myopic choroidal neovascularisation (CNV).
Methods: Twenty-nine eyes of 29 patients with myopic CNV were prospectively recruited to receive three initial monthly intravitreal bevacizumab injections. Three additional monthly injections were performed in eyes with persistent or recurrent CNV after 3 months.
Results: The mean spherical equivalent refractive error was −10.0 D. Sixteen eyes had previous photodynamic therapy (PDT) and 13 eyes had no prior PDT. All patients completed follow-up at 1 year. Following the initial three bevacizumab injections, 27 (93.1%) eyes had angiographic closure and two (6.9%) required further treatment. Two additional patients required re-treatment for CNV recurrence between 6 and 9 months. The mean baseline logarithm of the minimum angle of resolution (logMAR best-corrected visual acuity) was 0.62 (20/83), which improved to 0.38 (20/48) at 12 months (p<0.001). The mean visual improvement was 2.4 lines and 21 (72.4%) eyes had improvement of ⩾2 lines. Optical coherence tomography showed significant reduction in central foveal thickness following treatment. Eyes without previous PDT were more likely to gain ⩾2 lines after treatment than eyes that had previous PDT (p = 0.010).
Conclusions: The 1-year outcomes confirmed the results of previous short-term studies that intravitreal bevacizumab is effective for myopic CNV, with a high proportion of patients sustaining visual gain after treatment.
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Choroidal neovascularisation (CNV) is one of the most sight-threatening complications in patients with pathological myopia (PM).1 2 If left untreated, the visual prognosis is generally poor and a high proportion of patients will develop visual loss.3 Photodynamic therapy (PDT) with verteporfin was the first therapy to gain widespread use in the treatment of myopic CNV, as several studies showed that PDT can reduce the risk of visual loss.4–6 However, despite PDT, more than 50% of patients still had persistent CNV leakage at 12 months and 13% developed visual loss of three lines or more at 1 year.5–7 Combination treatment using PDT with intravitreal triamcinolone acetonide has also been attempted to improve the treatment outcome, but results have been variable.8 9 Therefore, the current strategy using PDT for myopic CNV is still suboptimal.
Recently, anti-angiogenesis therapy with the use of anti-vascular endothelial growth factor (VEGF) agents has gained increasing popularity in treating CNV. Intravitreal injection of an anti-VEGF drug, bevacizumab, appears to be effective in treating CNV due to age-related macular degeneration (AMD).10–12 A number of studies have also demonstrated the short-term efficacy of intravitreal bevacizumab in treating CNV secondary to PM.13–17 However, all these studies only reported on a follow-up of up to 6 months and the longer term visual outcome and recurrence rate remained unclear. Here, we report the outcome of a 1-year prospective study to evaluate the use of intravitreal bevacizumab in the treatment of myopic CNV.
This was a prospective case series in which patients with CNV secondary to PM were recruited from the Department of Ophthalmology and Visual Sciences (Chinese University of Hong Kong) and Department of Ophthalmology (Hong Kong Sanatorium Hospital) from November 2005 to January 2007. The inclusion criteria included: spherical equivalent refractive error of −6.0 D or more; subfoveal or juxtafoveal CNV location; best-corrected visual acuity (BCVA) of 20/400 or better; and evidence of CNV was leakage on fluorescein angiography (FA). Exclusion criteria included features suggesting the CNV was secondary to AMD, angioid streaks, trauma, choroiditis, hereditary diseases in the study or fellow eye, or PDT within the past 6 months. The study was approved by both institutions and informed consent was obtained after discussing the risks, benefits and alternatives. The study was carried out in adherence to the tenets of the Declaration of Helsinki. The 6-month results of the first 22 patients have been reported previously.17
At baseline, BCVA was measured with ETDRS logarithm of the minimum angle of resolution (logMAR) chart at 4 m or Snellen chart at 6 m being converted to logMAR equivalent for analysis. Optical coherence tomography (OCT) was performed by technicians with Stratus OCT (Carl Zeiss Meditec, Dublin, CA, USA) using the line mode with 5 mm vertical and horizontal scans over the fovea; the central foveal thickness (CFT) was measured manually using the retinal thickness mode. Fundus photography and FA were performed, with the CNV lesion size and composition noted.
All patients were scheduled for three monthly intravitreal bevacizumab injections at baseline, 1 month and 2 months. Additional courses of intravitreal bevacizumab injections were performed in eyes with persistent or recurrent CNV angiographic leakage after 3 months and were given as blocks for three monthly injections. Intravitreal injection of 1.25 mg bevacizumab (Avastin; Roche, Basel, Switzerland) in 0.05 ml was carried out in an outpatient setting using a 30-gauge needle at 4 mm post-limbus. Bevacizumab was kept refrigerated at 4°C and directly withdrawn from the vial immediately before each injection. Any unused drug was discarded after the vial had been open for 4 h. Patients were given topical 0.5% levofloxacin (Cravit, Santen, Japan) four times per day for 2 weeks after each injection.
Follow-up visits were arranged 1 week after bevacizumab injection then every month with examinations performed as with baseline. Fundus photography and FA were performed at 3 and 6 months. Additional angiography was performed after 6 months in patients with persistent leakage or symptoms or signs suggestive of CNV recurrence. The main outcome measures were BCVA, OCT CFT, and angiographic findings during the 12 months. Any ocular or systemic adverse events were also recorded. Statistical analysis was performed using SPSS v.15.0 (SPSS Inc., Chicago, IL, USA). Serial changes in BCVA and OCT CFT were compared using Wilcoxon signed-ranks test and two-tailed t test respectively. A p value of <0.05 was considered as statistically significant.
Twenty-nine eyes of 29 patients were recruited. The mean age of the patients was 48.9 (SD 15.3, range 26–76) years. The mean spherical equivalent refractive error was −10.0 (SD 3.5, range −6.0 to −18.0) D and the mean duration of visual symptoms prior to treatment was 1.9 (range 0.5–5) months. All patients were of Chinese ethnicity. Twenty-seven eyes were phakic and two eyes were pseudophakic. Twenty-five (86.2%) CNV were subfoveal and four (13.8%) were juxtafoveal. All CNV were predominately classic in angiographic appearance and the mean CNV size was 0.7 disc area. Thirteen (44.8%) eyes had previous PDT and the mean number of PDT among these eyes was 2.7 (range 1–6) sessions. All patients completed follow-up at 12 months and received the scheduled three monthly intravitreal bevacizumab injections.
Visual outcome and number of treatments
The mean number of injections during the 12-month period was 3.6 (range 3–12). Twenty-five (86.2%) patients required only three intravitreal bevacizumab injections during the follow-up period and four (13.8%) required additional intravitreal bevacizumab injections after 3 months. The changes in mean logMAR BCVA during the study are shown in fig 1. At baseline, the mean logMAR BCVA was 0.62 (SD 0.26) (Snellen equivalent of 20/83). At 1 month, the mean logMAR BCVA significantly improved to 0.41 (SD 0.24) (Snellen equivalent of 20/51) (Wilcoxon signed-ranks test, p<0.001). At 12 months, the mean logMAR BCVA was 0.38 (SD 0.31) (Snellen equivalent of 20/48) (Wilcoxon signed-ranks test, p<0.001) and the mean improvement was 2.4 (range −3 to 10) lines. Twenty-three (79.3%) eyes had visual improvement of at least one line after treatment, with 21 (72.4%) eyes improved by two or more lines. One (3.4%) eye developed visual loss of three lines due to CNV with subfoveal scar formation after receiving six intravitreal bevacizumab injections in the first 6 months.
OCT and FA
The mean CFT at baseline was 276 (SD 103) μm and at 1 month after treatment, the mean CFT was reduced to 233 (SD 90) μm (two-tailed t test, p<0.001) (fig 2). At 3 months, the mean CFT was further reduced to 221 (SD 97) μm and it stabilised at about 233 μm from 6 months to 12 months. FA at 3 months showed absence of angiographic leakage in 27 (93.1%) eyes and two patients had persistent leakage from the CNV and required three additional intravitreal bevacizumab injections between 3 and 6 months. Of the 27 patients with absence of angiographic leakage at 3 months, two patients developed recurrence between 6 and 9 months and were given additional bevacizumab injections. At 12 months, CNV regression with absence of late CNV staining on FA was noted in 15 (51.7%) eyes and the CNV became fibrosed with late staining on FA in 13 (44.8%) eyes. One (3.4%) eye still had mild leakage from the CNV at 12 months despite having a total of 12 injections. An example of the angiographic and OCT changes after intravitreal bevacizumab injections is shown in fig 3.
Influence of prior PDT on visual outcome
Subgroup analysis was performed to assess the influence of prior PDT on the visual outcome of the patients. Intravitreal bevacizumab was performed for recurrent CNV in eyes which had previous PDT more than 6 months prior to bevacizumab injection. The baseline characteristics of eyes with or without prior PDT were similar in terms of mean age, spherical equivalent refractive error, baseline lesion size, and baseline mean logMAR BCVA (all p>0.3). Eyes without prior PDT were more likely to gain two or more lines of vision at 12 months after treatment compared with eyes that had prior PDT, with 15 (93.8%) of 16 eyes compared with six (46.2%) of 13 eyes respectively (Fisher’s exact test, p = 0.010). Moreover, eyes that had not received previous PDT had a mean visual improvement of 3.7 lines, compared with a mean improvement of 2.0 lines for eyes that had previous PDT (Mann–Whitney U test, p = 0.036).
None of the patients developed any systemic complications related to intravitreal bevacizumab. Ocular complications, such as intraocular inflammation, increase in intraocular pressure (IOP) and an increase in incidence of cataract and endophthalmitis, were not observed. One patient was found to have an increase in myopic foveoschisis on OCT during the follow-up period. Despite this, the patient gained two lines of vision compared with baseline after CNV regression. Another patient was found to have a peripheral retinal tear at 6 months after the first injection that may or may not have been related to the intravitreal injections. The patient was treated with laser photocoagulation and no retinal detachment developed subsequently.
Bevacizumab is a recombinant full length anti-VEGF monoclonal antibody that binds to all isoforms of VEGF-A and was initially developed for metastatic colon cancer.18 In ophthalmology, intravitreal bevacizumab injection was first used for treating neovascular AMD; its use has now been extended to CNV of various causes, including CNV secondary to central serous chorioretinopathy,19 ocular inflammation,20 21 ocular histoplasmosis21 and pseudoxanthoma elasticum.22 23 Several studies have also reported the short-term results of intravitreal bevacizumab for myopic CNV.13–17 Yamamoto et al reported that eight (72.7%) of 11 eyes that received intravitreal bevacizumab achieved vision of 20/50 or better after a mean follow-up of 5 months.13 In another study by Sakaguchi et al,14 six (75%) of eight eyes that received intravitreal bevacizumab had visual improvement of two or more lines after follow-up of up to 7 months. Mandal et al reported the results of 12 eyes in 11 patients who had intravitreal bevacizumab for myopic CNV.15 Patients were given repeated injections at 4-week intervals if OCT showed the presence of intraretinal oedema or subretinal fluid. At 6 months, the mean BCVA improved from 20/235 to 20/71 and 75% of eyes had improvement of three or more lines. In another study by Hernandez-Rojas et al,16 14 patients underwent a single intravitreal injection of 2.5 mg bevacizumab for myopic CNV and patients were followed for 6 months. Treatment resulted in significant visual improvement with mean BCVA improved from 20/200 at baseline to 20/60 at 3 months. Similarly to our previous pilot study,17 we showed that three monthly intravitreal bevacizumab injections resulted in mean improvement of 2.6 lines, with 68.2% gaining two or more lines at 6 months. However, despite these promising results, patients were only followed for up to about 6 months and the longer term results remained uncertain.
In our present study, we extended the follow-up duration to 12 months and recruited additional patients to further evaluate the efficacy of intravitreal bevacizumab in treating myopic CNV. Our results showed that three initial monthly intravitreal bevacizumab injections followed by additional injections in patients with persistent or recurrent CNV resulted in a mean visual improvement of 2.4 lines at 12 months, with 21 (72.4%) eyes having improvement of two or more lines. Anatomical improvement in terms of mean OCT CFT reduction was also observed. These findings are consistent with previous short-term studies showing that intravitreal bevacizumab is effective in treating myopic CNV, with a high proportion of patients having visual improvement. The results are very encouraging, as the previous study on the use of PDT with verteporfin could only achieve a mean visual improvements of 0.2 lines at 12 months.5 Moreover, by giving three initial monthly intravitreal bevacizumab injections, we were able to archive CNV closure with cessation of angiographic leakage in 27 (93.1%) eyes. This rate is superior compared with PDT, in which persistent CNV leakage was seen in 91% of eyes at 3 months following a single PDT.7
Our subgroup analysis of eyes with or without previous PDT showed that intravitreal bevacizumab appeared to result in more visual gain in patients without previous PDT. This might be due to pre-existing retinal damage associated with previous CNV episode or pre-existing retinal pigment epithelial (RPE) or retinal damage caused by previous PDT. Parodi et al have shown that eyes with PM had preexisting RPE atrophy around the CNV and PDT might further worsen the RPE atrophy.24 Chen et al also demonstrated that eyes which had more than one PDT were less likely than eyes which had a single treatment to have visual improvement after treatment as repeated PDT may cause collateral damage to the choriocapillaris, RPE and the retina.25 The authors suggested that alterative treatment modality like anti-VEGF should be considered.
Our current study and previous studies have shown that intravitreal bevacizumab injections for myopic CNV are generally safe. Nonetheless, one patient in our series developed an increase in myopic foveoschisis after treatment and another patient developed a peripheral retinal break that required barrier laser photocoagulation. We could not determine whether these adverse events were caused by the treatment as they could also develop as part of the natural history of highly myopic eyes. Despite these adverse events, both patients had visual gain at 12 months after treatment. Without the use of intravitreal bevacizumab, CNV progression might have resulted in visual loss. Therefore, we believe that intravitreal bevacizumab is still warranted in these highly myopic eyes despite the possible risks of adverse events. In view of the increased risk of retinal complications, patients should be warned of the potential complications; clinicians should perform detailed retinal examinations and should consider prophylactic barrier laser treatment in high-risk patients prior to intravitreal injections.
Despite this study having the longest follow-up to date in evaluating the use of intravitreal bevacizumab for myopic CNV, our study contains several weaknesses. The most important limitation was the lack of a control group with previously established therapy such as PDT for comparison. However, unlike PDT, short-term outcomes of previous studies all demonstrated that intravitreal bevacizumab for myopic CNV could result in visual gain. Therefore, it might not be appropriate to continue treating patients with PDT in view of the promising results of intravitreal bevacizumab. Second, the 12-month follow-up period is still relatively short considering the natural history of the disease and therefore the long-term treatment efficacy remains to be determined. Third, the optimal dosage, number and frequency of intravitreal bevacizumab injections remains uncertain. We performed three intravitreal bevacizumab injections at monthly intervals in an attempt to consolidate the treatment effect and to minimise the risk of CNV persistence or recurrence. Fourth, the small sample size may skew the results in the subgroup analysis on eyes with or without prior PDT. Last, we used a re-treatment protocol of three additional injections instead of a single injection. We believe this protocol might be more suitable in myopic CNV: it is hard to solely rely on monthly OCT assessment for making re-treatment decisions, as myopic CNV is usually not associated with marked subretinal fluid. In view of the encouraging results from this 12-month prospective study, further large-scale studies to evaluate the safety and efficacy of intravitreal bevacizumab or other anti-VEGF agents in patients with myopic CNV are warranted.
Funding: upported by Competitive Earmarked Research Grant #4140/02M.
Competing interests: None declared.
Ethics approval: Obtained.
Patient consent: Obtained.
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