Analysis of therapeutic effect of intravitreal ranibizumab for the treatment of active wet age-related macular degeneration with hemorrhagic presentation from the outset: A Welsh experience

Dear Editor, Submacular and in particular subfoveal hemorrhage secondary to neovascular active wet age-related macular degeneration (ARMD) is one of the common complications that carries a very poor prognosis in terms of anatomical improvement in macular structure and eventual visual outcome.[1,2] Active leaking choroidal neovascular membrane (CNVM) with submacular or subfoveal hemorrhage ≥50% of total lesion area and one or more disc area in size had been traditionally excluded from landmark intravitreal antivascular endothelial growth factor (anti-VEGF) licensing trials.[3,4] There are only a few published literature that show the rationality of therapeutic efficacy and favorable outcome with submacular or subfoveal hemorrhage by intravitreal anti-VEGF treatment alone in terms of stabilization of visual acuity (VA) and macular anatomical outcome.[5,6] However, such patients were not routinely excluded from treatment with regular intravitreal anti-VEGF drug administration in day-to-day clinical practice for initiating management in view of restoring and/or stabilizing VA and macular anatomical structure. The author aimed to assess the efficacy of a licensed intravitreal anti-VEGF drug: ranibizumab used for the treatment of hemorrhagic type of wet ARMD in a retrospective study which included a total of 88 eyes over a period of 24 months. Thus, in a retrospective analysis, the author proposes that the presence of any extent of submacular and/or subfoveal hemorrhage in active neovascular/wet ARMD does not preclude the possibility of substantial visual improvement and should not be regarded as an exclusion criterion for intravitreal treatment with licensed anti-VEGF drug; ranibizumab. The author conducted a comparison outcome of intravitreal ranibizumab (LucentisR: Genentech, USA) treatment between the study group of hemorrhagic presentation and a comparator group of nonhemorrhagic presentation of active Wet ARMD patients in a tertiary ophthalmology department in Wales, United Kingdom, from January to December in 2015. Anonymous data were obtained from the electronic patient record, Medisoft ophthalmologyR (Medisoft Limited, Leeds, UK). 88(= n) eyes with active wet ARMD had been treated with ranibizumab. Thirty-seven eyes presented with active disease associated with any extent of submacular and/or subfoveal hemorrhage from the outset and the remaining 51 eyes presented without any form of macular hemorrhage. Patients treated with other form of anti-VEGF had been excluded from this study. Comparisons were made between those two groups in relation to VA gain in Logarithm of the Minimum Angle of Resolution (LogMAR) scale, central retinal thickness (CRT) achieved in micron, and number of ranibizumab intravitreal injection treatment given at the point of initial baseline presentation followed by at 3rd, 6th, 12th, and finally 24th month. ClinCalc online calculation tool (clincalc.com/tats/sample size; ClinCalc LLC, 2019, USA)[7] was used to determine the required sample size for the purpose of power calculation and to validate the hypothesis aiming to accept or reject to yield any statistically significant differences between those two groups. The following parameters were used, estimated mean (±standard deviation) LogMAR VA for Group 1 (macular hemorrhage) 0.5 ± 0.15 and the same for Group 2 (macular nonhemorrhage) 0.4; α =0.05; power = 80%. The required sample size was calculated as 70 subjects, so a minimum of 35 subjects were planned in each group to be compared. The sample size of the present study: n = 88, allocated into two different arms of the study (study group: macular hemorrhage = 37 and control group: macular nonhemorrhage = 51), satisfying the above-anticipated calculation to validate the test result. Two-tailed-Student’s-t-test with two samples of unequal variance was performed between those two groups in Microsoft Office ExcelR statistical software. P ≤ 0.05 was considered to be statistically significant in the null hypothesis, assuming no difference between data obtained from those two groups. P values of VA in LogMAR scale between the study group and comparator group at 3rd, 6th, 12th, and 24th month were 0.74, 0.43, 0.62, and 0.43, respectively. P values of CTR in micron between those two groups were 0.78, 0.12, 0.61, and 0.75, respectively. P values of a number of ranibizumab injection given between those two groups were 0.06, 0.74, 0.54, and 0.76, respectively. Figures 1-3 are three graphical representations of comparison for the chosen parameters obtained between two groups during this study.Figure 1: Mean visual acuity hem/nonhem comparison graphFigure 2: Mean central retinal thickness hem/nonhem comparison graph. CRT: Central retinal thicknessFigure 3: Mean number of injection Hem/nonhem comparison graphP values yielded for each parameter considered above were >0.05, implying the acceptance of the proposed Null Hypothesis of no difference of outcome at different time points considered above. The visual improvement achieved by the group of patients with hemorrhagic presentation at the outset was almost comparable with and certainly no inferior to the group of patients with nonhemorrhagic presentation after having been treated with a standard licensed anti-VEGF drug: ranibizumab; implying its renewed and ongoing relevance to treat the condition since approval in 2006 by the United States Federal Drug Administration despite the availability of several other newer generation licensed intravitreal anti-VEGF drugs being used currently. The prognosis and the final visual outcome of neovascular wet-ARMD with submacular and/or subfoveal hemorrhage are poor and lesions with more than 50% blood have always been excluded in all large Phase III clinical trials so far. In this retrospective study, the report of the effectiveness of standard anti-VEGF, ranibizumab, monotherapy as a treatment option for active leaking CNVM complicated with hemorrhage regardless of extension and type, in comparison to nonhemorrhagic presentation is certainly encouraging. This comparison study especially with the control group of wet-ARMD without any submacular hemorrhage and with a good number of patient’s pool did not obtain any statistically significant differences as long-term outcome in VA gain, CRT improvement, and number of intravitreal treatment administered for a good length of time. Although this study was based on the outcome of 2-year period in a single center, subsequent further long-term outcome determination was beyond the scope of the study and the inference may not be considered an absolute conclusion. However, it would give us definite insight in relation to the future prognosis of the treatment as there was not enough evidence to substantiate the effectiveness of anti-VEGF monotherapy alone, even after being licensed for treatment for more than a decade, especially in hemorrhagic presentation of wet-ARMD from the outset.[8] Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.