Ranibizumab Treatment for Neovascular AMD
We related the responsiveness to intravitreal ranibizumab in our study to the initial lesion size at baseline. Lux et al. showed that the efficiency of intravitreal bevacizumab in patients with neovascular AMD depended on the initial lesion size. This outcome corresponds with the findings of the TAP and VIP trials, which also reported the initial lesion size as an important predictor of the magnitude of treatment benefit with verteporfin therapy in occult, with no classic or minimally classic lesion, compositions.
Before the use of ranibizumab, treatments, such as verteporfin photodynamic therapy (Visudyne, Novartis Pharmaceuticals, Nürnberg, Germany) and laser photocoagulation merely slowed the progression of visual acuity loss.
Although intravitreal injections of ranibizumab have been shown to be effective in the treatment of neovascular AMD, not all patients demonstrated improvements in visual acuity, and some had lost ≥3 lines of VA by the end of the MARINA and ANCHOR trials.
In this study performed in a clinical setting, 35% of the patients were considered to be reduced responders to treatment at the end of follow-up, having either reduced visual acuity compared to baseline and/or persistent intraretinal or subretinal fluid or persistent or recurrent choroidal neovascularisation.
In a cohort receiving as-needed injections of ranibizumab for exudative AMD, visual improvement was related to the frequency of injections received but not to the resolution of fluid by OCT. Ahlers and co-workers identified subretinal fluid as the most relevant factor for visual function.
Brown et al. stated that if a monthly reinjection protocol is not used and patients are treated on an as-needed basis, a combination of clinical examination and qualitative OCT measurements should be used to guide the anti-VEGF treatment to maximise vision gain. The importance of closely monitoring patients is confirmed by our study, as 35% of the patients presented a reduction in visual acuity compared to baseline and/or persistent intraretinal or subretinal fluid or persistent or recurrent choroidal neovascularisation at the end of follow-up.
Menghini et al. retrospectively evaluated predictive factors for being a "good" or "bad" responder to ranibizumab treatment. They found that only the course of visual acuity in the first three months seems to be of value for estimating the treatment response; however, they identified no predictor for response to treatment, e.g. lesion size.
Rosenfeld and co-workers investigated the cause of visual acuity (VA) loss in patients with neovascular age-related macular degeneration (AMD) receiving monthly ranibizumab injections in pivotal ranibizumab phase-III trials. At month 24, 9% of the ranibizumab-treated patients from MARINA and 10% of the ranibizumab-treated patients from ANCHOR had lost >/=15 letters VA. Baseline characteristics associated with VA loss at month 24 included older age, better VA, and larger lesions.
Surprisingly, unlike other authors, we did not find a correlation between age and a reduced response to treatment. However, other investigators have also not found a correlation between age and response to treatment. Our findings should be verified in a larger population with a longer follow-up.
Defining the proportion of reduced responders in the MARINA and ANCHOR trials is not entirely possible, as both report the proportion of patients improving by more than 15 letters, and the primary end point was the proportion of patients losing fewer than 15 letters. The proportions of patients improving by more than 15 letters were 33.8% for the 0.5 mg group in the MARINA study and 40.3% for the 0.5 mg group in the ANCHOR study. In our study, only one patient (0.6%) lost three or more lines of vision at the end of follow-up; conversely, 99.4% of patients lost fewer than three lines. In the MARINA and ANCHOR trials, this proportion was 94.6% in the 0.5 mg group in the MARINA and 96.4% in the 0.5 mg group in the ANCHOR study. In our study, we observed only 17.6% of patients with improvement by more than 3 lines, but one must consider that we included all CNV types, including those with RAP lesions and the 12.1% of patients with a pigment epithelium detachment at baseline. Thus, the results are difficult to compare. Reche-Frutos et al. stated that RAP II lesions with PED and RAP III have an poorer anatomic and visual evolution than patients with stage II without PED after ranibizumab therapy. Another difference is that we had a follow-up of six months, whereas the MARINA and ANCHOR studies had 12 months of follow-up.
Muether and co-workers found a correlation between the time elapsed between treatment indication and first injection and the visual acuity deterioration. Other authors reported a correlation between visual acuity deterioration in 28.4% of patients and a median treatment delay of 28 days. In our study, the time elapsed between the diagnosis and the first ranibizumab treatment was not a predictor of a reduced response to treatment, according to the criteria listed above. In Germany, payment for the initial ranibizumab treatment and PRN treatment must be pre-approved by the patient's public health insurance company. In Germany, the predominantly visual acuity-driven ranibizumab retreatment regimen is based on the EMA (European Medicines Agency) drug information, which recommends retreatment after recurrent vision loss of 5 EDTRS letters. Second, lesion activity (persistent or recurrent subretinal fluid, increase of pigment epithelium detachment, new haemorrhage, recurrent thickening of the retina >100 μm) was recommended as an important criterion for retreatment by the German Ophthalmological Society (DOG), the Professional Association of German Ophthalmologists (BVA) and the Retinological Society (RG).
Because we defined reduced responders as patients with either decreasing visual acuity at the end of follow-up or a reduced anatomical response to treatment, those patients who experienced a delay in the onset of therapy may have already had further alterations in the retinal pigment epithelium or fibrosis. However, in our study, visual acuity at baseline was no predictor of a reduced response to treatment.
Our study is limited by its retrospective nature, and a further weakness is the limited follow-up of six months. In Germany, reimbursement for the OCT is not covered by public health insurance. Therefore, as the patient has to pay for the OCT, it was not performed every four weeks. Moreover, the present study did not differentiate the extent of fibrosis as a predictor for reduced response to treatment. The presence of active choroidal neovascularisation was an inclusion criterion for enrolment in the study; thus, further studies investigating the presence and extent of fibrosis in the analysis of predictors are needed. Another limitation of our present study is its short follow-up, as large lesions in this short time period might not have been sufficiently treated. Furthermore, large initial lesion sizes might simply reflect a more severe nature of the disease than smaller lesion sizes, rather than a reduced response to treatment. Further studies with a longer follow-up will be necessary to verify whether lesion size is truly a predictor of reduced response.
The "reduced responder" poses challenges to clinicians, and there is no general consensus on how "reduced responders" are defined. The existing studies are very heterogeneous, and comparisons with published studies are difficult. The definition of a "reduced responder" in our study was chosen as stated above in order to include patients with decreasing visual acuity at the end of follow-up, as well as those showing a reduced anatomical response to treatment.
Discussion
We related the responsiveness to intravitreal ranibizumab in our study to the initial lesion size at baseline. Lux et al. showed that the efficiency of intravitreal bevacizumab in patients with neovascular AMD depended on the initial lesion size. This outcome corresponds with the findings of the TAP and VIP trials, which also reported the initial lesion size as an important predictor of the magnitude of treatment benefit with verteporfin therapy in occult, with no classic or minimally classic lesion, compositions.
Before the use of ranibizumab, treatments, such as verteporfin photodynamic therapy (Visudyne, Novartis Pharmaceuticals, Nürnberg, Germany) and laser photocoagulation merely slowed the progression of visual acuity loss.
Although intravitreal injections of ranibizumab have been shown to be effective in the treatment of neovascular AMD, not all patients demonstrated improvements in visual acuity, and some had lost ≥3 lines of VA by the end of the MARINA and ANCHOR trials.
In this study performed in a clinical setting, 35% of the patients were considered to be reduced responders to treatment at the end of follow-up, having either reduced visual acuity compared to baseline and/or persistent intraretinal or subretinal fluid or persistent or recurrent choroidal neovascularisation.
In a cohort receiving as-needed injections of ranibizumab for exudative AMD, visual improvement was related to the frequency of injections received but not to the resolution of fluid by OCT. Ahlers and co-workers identified subretinal fluid as the most relevant factor for visual function.
Brown et al. stated that if a monthly reinjection protocol is not used and patients are treated on an as-needed basis, a combination of clinical examination and qualitative OCT measurements should be used to guide the anti-VEGF treatment to maximise vision gain. The importance of closely monitoring patients is confirmed by our study, as 35% of the patients presented a reduction in visual acuity compared to baseline and/or persistent intraretinal or subretinal fluid or persistent or recurrent choroidal neovascularisation at the end of follow-up.
Menghini et al. retrospectively evaluated predictive factors for being a "good" or "bad" responder to ranibizumab treatment. They found that only the course of visual acuity in the first three months seems to be of value for estimating the treatment response; however, they identified no predictor for response to treatment, e.g. lesion size.
Rosenfeld and co-workers investigated the cause of visual acuity (VA) loss in patients with neovascular age-related macular degeneration (AMD) receiving monthly ranibizumab injections in pivotal ranibizumab phase-III trials. At month 24, 9% of the ranibizumab-treated patients from MARINA and 10% of the ranibizumab-treated patients from ANCHOR had lost >/=15 letters VA. Baseline characteristics associated with VA loss at month 24 included older age, better VA, and larger lesions.
Surprisingly, unlike other authors, we did not find a correlation between age and a reduced response to treatment. However, other investigators have also not found a correlation between age and response to treatment. Our findings should be verified in a larger population with a longer follow-up.
Defining the proportion of reduced responders in the MARINA and ANCHOR trials is not entirely possible, as both report the proportion of patients improving by more than 15 letters, and the primary end point was the proportion of patients losing fewer than 15 letters. The proportions of patients improving by more than 15 letters were 33.8% for the 0.5 mg group in the MARINA study and 40.3% for the 0.5 mg group in the ANCHOR study. In our study, only one patient (0.6%) lost three or more lines of vision at the end of follow-up; conversely, 99.4% of patients lost fewer than three lines. In the MARINA and ANCHOR trials, this proportion was 94.6% in the 0.5 mg group in the MARINA and 96.4% in the 0.5 mg group in the ANCHOR study. In our study, we observed only 17.6% of patients with improvement by more than 3 lines, but one must consider that we included all CNV types, including those with RAP lesions and the 12.1% of patients with a pigment epithelium detachment at baseline. Thus, the results are difficult to compare. Reche-Frutos et al. stated that RAP II lesions with PED and RAP III have an poorer anatomic and visual evolution than patients with stage II without PED after ranibizumab therapy. Another difference is that we had a follow-up of six months, whereas the MARINA and ANCHOR studies had 12 months of follow-up.
Muether and co-workers found a correlation between the time elapsed between treatment indication and first injection and the visual acuity deterioration. Other authors reported a correlation between visual acuity deterioration in 28.4% of patients and a median treatment delay of 28 days. In our study, the time elapsed between the diagnosis and the first ranibizumab treatment was not a predictor of a reduced response to treatment, according to the criteria listed above. In Germany, payment for the initial ranibizumab treatment and PRN treatment must be pre-approved by the patient's public health insurance company. In Germany, the predominantly visual acuity-driven ranibizumab retreatment regimen is based on the EMA (European Medicines Agency) drug information, which recommends retreatment after recurrent vision loss of 5 EDTRS letters. Second, lesion activity (persistent or recurrent subretinal fluid, increase of pigment epithelium detachment, new haemorrhage, recurrent thickening of the retina >100 μm) was recommended as an important criterion for retreatment by the German Ophthalmological Society (DOG), the Professional Association of German Ophthalmologists (BVA) and the Retinological Society (RG).
Because we defined reduced responders as patients with either decreasing visual acuity at the end of follow-up or a reduced anatomical response to treatment, those patients who experienced a delay in the onset of therapy may have already had further alterations in the retinal pigment epithelium or fibrosis. However, in our study, visual acuity at baseline was no predictor of a reduced response to treatment.
Our study is limited by its retrospective nature, and a further weakness is the limited follow-up of six months. In Germany, reimbursement for the OCT is not covered by public health insurance. Therefore, as the patient has to pay for the OCT, it was not performed every four weeks. Moreover, the present study did not differentiate the extent of fibrosis as a predictor for reduced response to treatment. The presence of active choroidal neovascularisation was an inclusion criterion for enrolment in the study; thus, further studies investigating the presence and extent of fibrosis in the analysis of predictors are needed. Another limitation of our present study is its short follow-up, as large lesions in this short time period might not have been sufficiently treated. Furthermore, large initial lesion sizes might simply reflect a more severe nature of the disease than smaller lesion sizes, rather than a reduced response to treatment. Further studies with a longer follow-up will be necessary to verify whether lesion size is truly a predictor of reduced response.
The "reduced responder" poses challenges to clinicians, and there is no general consensus on how "reduced responders" are defined. The existing studies are very heterogeneous, and comparisons with published studies are difficult. The definition of a "reduced responder" in our study was chosen as stated above in order to include patients with decreasing visual acuity at the end of follow-up, as well as those showing a reduced anatomical response to treatment.
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