The current treatment of neovascular age-related macular degeneration (nAMD) generates an excessive care pressure in the public health system. The search for a satisfactory treatment regimen, whose anatomical and functional stability may be achieved, is a challenge and a goal to be reached. We analyzed the outcomes in a patient cohort under fixed regimen treatment with intravitreal aflibercept (IVA). A retrospective study, with at least 1-year follow-up, in consecutive treated unselected naïve patients was carried out. Standard protocol was performed and evaluated at baseline, month 4 (after loading dose, LD), and month 12 (after fixed bimonthly regimen). One hundred six patients (123 eyes) aged 80.3 ± 7.7 years were included, receiving 6.8 ± 0.7 IVA. Visual acuity gain after LD was 5.5 ± 12.0 letters (
Age-related macular degeneration (AMD) is the leading cause of visual impairment and blindness in developed countries [
Although several potential therapeutic targets exist, the main pharmacological treatment for nAMD is blocking the action of vascular endothelial growth factor (VEGF). Experience accumulated during everyday clinical practice with intravitreal therapy with anti-VEGF confirmed that real-life outcomes are generally less impressive than those reported in clinical trials [
Aflibercept has been shown to bind VEGF-A, VEGF-B, and placental growth factor (PGF) with higher affinity than the other currently available anti-VEGFs, presenting a longer intravitreal half-life, which may translate into less need for injection and follow-up controls [
Under this context, we have retrospectively analyzed the functional and structural outcomes achieved in an nAMD naïve-patient cohort who were treated with IVA for one year using a fixed bimonthly regimen. Our aim was to evaluate its effectiveness and optimize patient’s assessment in daily clinical practice in public specialized health care. We have analyzed the general results of our cohort, and a subanalysis study was conducted with the aim of verifying our visual and structural results in a real-world setting.
This was a retrospective, single-centre, observational study conducted in the service of ophthalmology of the Hospital Clínic de Barcelona (Barcelona, Spain), a community hospital that is part of the Catalan Public Hospital Network. The local Research Ethics Committee gave its approval (HCB/2018/1051) for the audit and retrospective evaluation of the electronic clinical history files, which was conducted according to the Declaration of Helsinki guidelines and Spanish data protection law (Ley Orgánica 05/2018). Patients provided written informed consent before starting intravitreal treatment.
Data from consecutive naïve patients with nAMD, including PCV or RAP [
In accordance with our standard normalized protocol, nAMD was diagnosed and classified on eye fundus examination and confirmed by spectral domain- (SD-; AngioPlex™, Carl Zeiss Meditec) or swept source- (SS-; Triton™ DRI, Topcon Inc.) optical coherence tomography (OCT). This protocol only allows other imaging modalities such as fluorescent angiography (FA) and indocyanine green angiography (ICGA) during follow-up in patients not responsive to treatment. Volumetric high-resolution OCT scans were acquired over a 6 × 6 mm field centred on the fovea to fully capture the lesion. OCT scans satisfied consensus criteria for retinal OCT quality assessment (OSCAR-IB) [
BCVA- and OCT-based outcomes assessed in this study are those at baseline, months 3-4 (after LD) and month 12 or 13 (after the 7th injection at month 11, at the end of the first year). Functional variables considered were mean change in BCVA, the number of eyes gaining ≥15 or losing ≤5 letters and achieving BCVA ≥20/40 (70 letters). The structural variables analyzed included the central subfoveal macular thickness (CMT)—defined as the macular average thickness in the central 1 mm of the ETDRS grid—the average macular thickness (AMT)—defined as the mean thickness for each of the nine sectors of the entire 6 mm ETDRS grid—and the presence of intraretinal fluid (IRF), intraretinal cysts, subretinal fluid (SRF), and pigment epithelial detachment (PED), as assessed by OCT. The presence of hemorrhage, as well as retinal pigment epithelium (RPE) atrophy and fibrosis, was detected by biomicroscopy macular examination. The percentage of eyes with dry macula, defined as absence of IRF or cysts, and SRF fluid on OCT was also determined. BCVA gain in the different nAMD subtypes was assessed in an exploratory analysis given the small number of patients with PCV or RAP expected. Subanalysis by age group was also performed, taking into account a normal distribution of the cohort and the balanced differences between the different groups as follows: (a) patients ≤77 and >77 years; (b) patients ≤80 and >80 years; (c) patients ≤83 and >83 years; (d) patients ≤85 and >85 years. Safety variables included injection-related, ocular-related, and systemic adverse events.
Patient and disease characteristics are described as continuous variables and expressed as mean (standard deviation [SD])/median (first and third quartiles [Q1; Q3]) and compared by the Mann–Whitney
A total of 106 patients (123 eyes) were included in the study. Mean age was 80.3 ± 7.7 years (range 58–98) and 62 (58.5%) were men. The nAMD was bilateral in 17 patients and 18 (14.6%) eyes belonged to patients aged ≥90 years. Nineteen (15.4%) and 20 (16.3%) eyes presented signs of PCV and RAP on SS- or SD-OCT [
Mean BCVA at baseline was 20/60 (58.7 ± 17.1 letters). Thirteen (10.6%) eyes had baseline BCVA <20/300 (25 letters): five eyes with 20/400 (20 letters) and 4 eyes with 20/800 (4 letters). After the LD, BCVA increased to 5.5 ± 12.0 letters (
Changes in BCVA (ETDRS letters), CMT (
Best-corrected visual acuity (number of letters) in overall cohort, after loading dose (LD) and at final follow-up period (12 mo).
Letters | LD | 12 mo | |
---|---|---|---|
Gain | 5 to 9 | 21 (17.1) | 20 (16.3) |
10 to19 | 26 (21.1) | 28 (22.8) | |
≥20 | 10 (8.1) | 12 (9.7) | |
Equal | 0 to 4 | 47 (38.3) | 33 (26.8) |
Loss | 1 to 4 | 3 (2.4) | 6 (4.9) |
5 to 9 | 8 (6.5) | 10 (8.1) | |
≥10 | 8 (6.5) | 14 (11.4) |
Letters: number of letters ETDRS;
Mean baseline BCVA was 54.5 ± 18.9, 56.3 ± 23.0, and 60.2 ± 15.0 letters in patients with RAP, PCV, and nAMD, respectively. BCVA gain after the LD was 7.7 ± 9.4 letters (
Mean CMT at baseline was 325.2 ± 104.1
Presence of retinal findings during the period of study. (a) Changes in the percentage of eyes with subretinal fluid (SFR), intraretinal fluid (IRF), and hemorrhages, at baseline, after the loading dose (LD), and at 12 months (12 mo), were significant (
Prevalence of eyes with hemorrhage, RPE atrophy, subretinal fibrosis, and dry macula at baseline, after the loading dose (LD), and at final follow-up period (12 mo).
Baseline | LD | 12 mo | ||||
---|---|---|---|---|---|---|
Hemorrhage | 54 (43.9) | 20 (16.3) | <0.0001 | 10 (8.1) | 0.0782 | <0.0001 |
RPE atrophy | 13 (10.6) | 32 (26.0) | 0.0027 | 45 (35.6) | 0.0986 | <0.0001 |
Fibrosis | 3 (2.4) | 9 (7.3) | 0.1361 | 16 (13.0) | 0.2048 | 0.0031 |
Dry macula | 12 (9.8) | 76 (61.8) | <0.0001 | 83 (67.5) | 1 | <0.0001 |
RPE: retinal pigment epithelium; LD: loading dose; 12 mo: final follow-up;
For this subanalysis, age groups have been considered taking into account a normal distribution of the cohort and the balanced differences between the different groups as follows: (a) patients ≤77 years (
Mean changes in BCVA at final follow-up and at the baseline were compared (Figure
Changes in BCVA (ETDRS letters) by age subgroup. (a) Patients ≤77 vs. >77 years. (b) Patients ≤80 vs. >80 years. (c) Patients ≤83 vs. >83 years. (d) Patients ≤85 vs. >85 years. Mean changes in BCVA after the loading dose (LD) and at the final follow-up were significant (
Best-corrected visual acuity (MD ± SD, number of letters) and gain (number of letters) at the baselines and at final follow-up period (12 mo) by age subgroup.
Age subgroup | Baseline | 12 mo | Gain | |
---|---|---|---|---|
≤77 y ( | 60.4 ± 18.5 | 66.1 ± 16.1 | 5.7 | 0.02 |
≤80 y ( | 60.3 ± 17.3 | 66.1 ± 15.0 | 5.8 | 0.009 |
≤83 y ( | 59.5 ± 18.3 | 65.1 ± 15.0 | 5.6 | 0.001 |
≤85 y ( | 60.0 ± 17.6 | 65.5 ± 14.7 | 5.5 | 0.008 |
>77 y ( | 58.4 ± 15.3 | 62.9 ± 13.4 | 4.5 | 0.004 |
>80 y ( | 57.9 ± 15.8 | 62.5 ± 13.8 | 4.6 | 0.008 |
>83 y ( | 58.3 ± 12.6 | 62.3 ± 13.2 | 4.0 | 0.02 |
>85 y ( | 56.9 ± 12.6 | 60.7 ± 13.2 | 3.8 | 0.07 |
y: age in years;
The presence of SRF-IRF and retinal hemorrhages has decreased significantly at the end of the study period (Figure
Presence of retinal findings during the period of study by age subgroups. (a) Changes in percentages of eyes with subretinal fluid (SFR), intraretinal fluid (IRF), and hemorrhages and (b) percentage of eyes presenting retinal pigment epithelium (RPE) atrophy and subretinal (SR) fibrosis, at baseline, after the loading dose (LD) and at 12 months (12 mo), were significant (
In our cohort, IVA was well tolerated. Severe adverse events were not observed, and mild adverse events were in line with its safety profile. Fourteen (11.4%) eyes required emergency care because of post-IVA floaters, superficial punctate keratopathy, and traumatic hyposphagma due to intraocular injection.
The results of our study support the effectiveness and safety of aflibercept, in a fixed regimen, for treatment-naïve patients with nAMD in clinical daily practice in a real-life scenario. The functional and structural benefits achieved confirm those of the two large pivotal clinical trials [
Contrary to the abovementioned studies, in accordance with everyday clinical practice in our setting, the only exclusion criteria in our study were those listed in the local summary product characteristics, with no restrictions with respect to baseline BCVA or the presence of structural damage to the fovea, or local or systemic comorbidities. These differences are likely to have had an effect on the visual outcomes achieved. Our study is also among the few to include patients with RAP and PCV, which has shown to be associated with differences in VA gain [
The mean age of the patients is among the highest compared to all previous studies with aflibercept. Unexpectedly, BCVA at the time of diagnosis was also among the highest, which likely reflects the effort made in our setting over the last years to speed referral from primary care to ophthalmology offices. Both higher age and higher BCVA at baseline are known to be associated with “ceiling effect” and then linked to lower VA gains [
Mean VA gain has been used as an outcome measure to assess efficacy in noninferiority clinical trials; however, more patient-centred measures of success may be preferred in studies in the real-world, including the percentage of patients who did not lose vision, or who gained ≥15 letters or maintained/achieved functional vision (i.e., ≥20/40 or 70 letters). After 12-month treatment, 88.6% of the patients in our study had not lost vision (i.e., had not lost ≥10 letters), 18.7% had gained ≥15 letters, and the percentage of patients maintaining or achieving a BCVA ≥70 letters had increased from 30.1% at baseline to 46.3%. As with the mean VA gain, these figures were slightly worse than those reported in pivotal studies [
Our study also reflects significant improvements in anatomic outcomes. As expected, there was a significant reduction in CMT after the LD, remaining stable up to month 12. Mean change in CMT and AMT at month 12 was lower than that reported in pivotal clinical trials [
Compliance with treatment and regular visits has also been shown to influence effectiveness of anti-VEGF therapy in the real world [
Our standard operating procedure for intravitreal treatment has been able to substantially reduce the number of follow-up visits (average 3 visits/year). Taking into account both the regular compliance with intravitreal treatment and the considerable decrease in healthcare pressure with fewer follow-up visits, treatment guidelines with a fixed regimen represent important advantages for the public healthcare system. Furthermore, our results have been able to demonstrate that the treatment based on a fixed regimen is capable of maintaining a high percentage of eyes with stable VA and anatomic profiles of the macula without IRF or SRF.
Despite that, our study has also several limitations, mostly related to the relatively small sample size and its retrospective nature, especially with regard to variables or confounding factors not collected (i.e., time from first symptoms to diagnosis and from diagnosis to treatment) that could have better explained the results observed. As previously remarked, potential PCV and RAP cases were not diagnosed at baseline, and therefore the differential outcomes according to type of nAMD are based on signs pointing to these nAMD variants. The effect of fellow eyes was not analyzed, which affected 17 eyes. The main strength of our analysis is that it was conducted in a single centre, with satisfactory level of compliance under a standardized protocol, thus ensuring the homogeneity of patient management.
The results of our study support the visual and anatomic benefits of fixed regimen of aflibercept in real-life clinical practice in naïve patients with nAMD. Significant improvements were achieved after the LD and maintained up to one year. Compliance with the bimonthly dosing and safety profile were generally satisfactory. These improvements are in agreement with those reported in other studies in clinical practice and support our management therapeutic protocol and logistic in public health specialized care.
The data used to support the findings of this study are available from the corresponding author upon request.
The authors declare that they have no proprietary interest regarding the publication of this paper.
The authors thank Beatriz Viejo, Ph.D., for her assistance in the writing of the manuscript and David Calbet for his statistical support. The authors also thank all optometric team members of their ophthalmological service for helping them in the clinical practice results observed in this study.