Wiener klinische Wochenschrift

, Volume 124, Issue 21, pp 750–755

The significance of early treatment of exudative age-related macular degeneration: 12 months’ results

Authors

  • Birgit Weingessel
    • Department of OphthalmologyHietzing Hospital
    • Karl Landsteiner Institute for Process Optimization and Quality Management in Cataract Surgery
  • Gregor Hintermayer
    • Department of OphthalmologySt. Poelten Hospital
  • Saskia M. Maca
    • Department of OphthalmologyHietzing Hospital
  • Renate Rauch
    • Department of OphthalmologyHietzing Hospital
    • Karl Landsteiner Institute for Process Optimization and Quality Management in Cataract Surgery
    • Department of OphthalmologyHietzing Hospital
    • Karl Landsteiner Institute for Process Optimization and Quality Management in Cataract Surgery
original article

DOI: 10.1007/s00508-012-0249-3

Cite this article as:
Weingessel, B., Hintermayer, G., Maca, S. et al. Wien Klin Wochenschr (2012) 124: 750. doi:10.1007/s00508-012-0249-3

Summary

Background

To assess whether the period between initial symptoms and therapy with ranibizumab in patients with choroidal neovascularization (CNV) influences visual outcome after a follow-up of 12 months.

Methods

Fifty patients with CNV were retrospectively split into three groups depending on the duration of visual symptoms: group I: < 1 month, group II: 1–6 months, and group III: > 6 months. Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were recorded at baseline, 2, 6, and 12 months. Patients received two initial intravitreal injections of 0.5 mg ranibizumab at baseline and reinjections as needed.

Results

The mean time span between initial symptoms and treatment was 66 ± 63 days. A longer duration of visual symptoms was significantly correlated with a lower BCVA at baseline, but also after 6 and 12 months.

Conclusions

Shorter duration of visual symptoms prior to treatment is associated with a better visual outcome.

Keywords

choroidal neovascularizationage-related macular degenerationas-neededduration of symptomsranibizumabtime to first treatment

Die Wichtigkeit einer frühen Behandlung bei exsudativer altersabhängiger Makuladegeneration – 12 Monats-Ergebnisse

Zusammenfassung

Hintergrund

Ziel dieser Studie war es, einen möglichen zeitlichen Einfluss zwischen Auftreten von Symptomen und Beginn einer Therapie bei choroidaler Neovaskularisation (CNV) auf das Sehvermögen nach einem Beobbachtungszeitraum von 12 Monaten herauszufinden.

Methodik

Fünfzig PatientInnen mit CNV wurden retrospektiv in drei Gruppen abhängig von der Symptomdauer geteilt: Gruppe I: < 1 Monat, Gruppe II: 1–6- Monate, Gruppe III: > 6 Monate. Der bestkorrigierte Visus und die zentrale Netzhautdicke wurden zu Beginn, nach 2, 6 und 12 Monaten erhoben. Die PatientInnen erhielten zwei initiale Injektionen mit 0,5 mg Ranibizumab in den Glaskörper. Weitere Injektionen wurden bei Bedarf verabreicht.

Ergebnisse

Die durchschnittliche Dauer zwischen Erstauftreten der Symptome und Beginn der Behandlung betrug 66 ± 63 Tage. Eine längere Symptomdauer korrelierte signifikant mit einem schlechteren Ausgangsvisus, aber auch mit einem schlechteren Sehvermögen nach 6 und 12 Monaten.

Schlussfolgerungen

Je kürzer die Symptomdauer vor Beginn der Behandlung ist, desto besser ist das Visusergebnis nach 12 Monaten.

Schlüsselwörter

choroidale Neovaskularisationaltersabhängige MakuladegenerationSymptomdauerRanibizumabBehandlungsbeginn

Introduction

Age-related macular degeneration (AMD) is the prevalent cause of moderate and severe vision loss in developed countries and the third major cause of blindness worldwide [13]. Visual loss in AMD is mainly caused by the development of choroidal neovascularization (CNV), which has been shown to occur in 18 % of patients within 5 years [4, 5]. In CNV new, fragile vessels grow from the choriocapillaris inward to the retina, leading to hemorrhages, edema, and finally scar formation associated with visual loss.

Since a few years, antiangiogenetic therapy is the first-choice treatment for neovascular AMD [3, 69]. Vascular endothelial growth factor (VEGF), a central mediator of angiogenesis and a potent permeability factor, seems to be one of the major stimuli for CNV in AMD [5, 10]. Ranibizumab (Lucentis®, Genentech, South San Francisco, CA) is a recombinant humanized antigen-binding antibody fragment (Fab) that neutralizes all known active forms of VEGF and was specifically designed for intraocular use [3, 11]. Several clinical key trials such as MARINA and ANCHOR have demonstrated the efficacy and safety of ranibizumab injections [6, 12]. With monthly injection, further deterioration of best-corrected visual acuity (BCVA) can be prevented in more than 90 % of patients and improved in approximately 40 % of patients for the entire spectrum of CNV subtypes [6, 1214]. A less frequent injection schedule with reinjections given as needed was investigated in several studies such as HORIZON or PRONTO [11, 15].

The daily growth rate of CNV in natural history was reported to be 10–18 mm on average [16, 17]. A deferral of initial therapy after onset of symptoms is suspected to have a negative effect on visual outcome [1821]. Muether et al. [18] reported a 1.1 logMAR line difference in vision loss for patients with a delay in treatment of less than 1 month compared with those with a delay of more than 1 month.

The short-time results of a previous study of our study group showed that two intravitreal injections of ranibizumab improved BCVA in all patients with CNV, but a longer duration of AMD as measured by the subjective duration of visual symptoms was associated with a worse visual outcome after treatment [22]. This is the rationale to investigate in the long-term results with a follow-up of 12 months to find out, if there is still a difference in visual outcome.

This study aimed to evaluate possible differences in visual outcome concerning the time between onset of symptoms and initial treatment after a follow-up period of 12 months.

Methods

Fifty individuals diagnosed with new-onset CNV were collected retrospectively at the Department of Ophthalmology of Hietzing Hospital, Vienna, Austria.

Patients with a subfoveal CNV showing activity, for instance, presence of retinal hemorrhage, intraretinal edema, subretinal fluid, or fibrovascular pigment epithelial detachment (PED) were consecutively included. Diagnosis of CNV was based on fluorescein angiography criteria.

For inclusion into the study, patients had to be able to precisely state the onset and kind of visual symptoms (visual distortion, changes in color vision, or development of central blurring of vision).

All patients received two initial intravitreal injections of ranibizumab (Lucentis®, Genentech, South San Francisco, CA) at an interval of 4 weeks. Further treatment was administered when progression of the disease was seen during the monthly controls. Retreatment with ranibizumab was performed, if one of the following changes was observed between visits: new intra- or subretinal fluid, visual loss of at least one line using Snellen charts in conjunction with persistent intraretinal or subretinal fluid in the macula as detected by optical coherence tomography (OCT), an increase in OCT central retinal thickness (CRT) of at least 100 mm, and new macular hemorrhage.

Patients were excluded from the study if the CNV was not subfoveal or not related to AMD, if it was a RAP lesion, if they were not able to give precise information upon visual symptoms, or if they had received any other treatment than two injections of ranibizumab at baseline.

The following parameters were obtained from each patient’s chart monthly: BCVA using Snellen charts, intraocular pressure (IOP) as measured by applanation tonometry, findings documented by indirect dilated fundus examination, and CRT as measured by OCT (Spectralis® OCT, Heidelberg Engineering, Heidelberg, Germany).

The type of subfoveal CNV was classified by fluorescein angiography (Spectralis® HRA + OCT, Heidelberg Engineering, Heidelberg, Germany) at baseline for accurate diagnosis of the disease.

According to the duration of visual symptoms, patients were allocated to one of three groups: group I: visual symptoms < 1 month, group II: 1–6 months, and group III: > 6 months.

Intravitreal injections were performed under aseptic conditions, according to the directions of several studies regarding the efficacy and safety of intravitreal injections [6, 12, 13]. Using a 30-gauge needle at baseline, 0.5 mg (0.05 ccm) of ranibizumab was injected via pars plana, and after 4 weeks further injections were administered as needed.

Data were analyzed using PASW Statistics 17.0.2 (SPSS Inc., Chicago, IL, USA). Nonparametric correlations were calculated using the Spearman-rho test. For comparing differences in mean value and standard deviation of variables, a two-tailed paired t-test was performed. Statistical significance was considered to be present at 5 %. This study was approved by the Ethics Committee of the city of Vienna. Written, informed consent was obtained from all participants, and the study was in adherence to the tenets of the Declaration of Helsinki.

Results

Fifty patients were included in the study, eight patients did not complete the 1-year follow-up, and so 42 patients were included in the statistical analyses. The mean age of patients with complete data was 78.2 ± 8.9 years; the majority of patients being women (69 %, n = 29).

Mean baseline BCVA was 0.35 ± 0.19 Snellen (median 0.30, range 0.05–0.8), patients reported to notice visual symptoms for a mean of 66 ± 63 days (median 51 days, range 1–212 days). A longer duration of visual symptoms was correlated with a lower BCVA at first presentation (r = 0.58, p < 0.001). Mean baseline CRT was 448 ± 118 mm (median 436.5 mm, range 205–773 mm).

Baseline characteristics of the three groups are shown in Table 1.The three groups did not differ from each other regarding race, gender distribution, and mean age.

Table 1

Baseline characteristics of the three groups regarding the duration of symptoms

 

Age (years)

Symptoms (days)

Baseline BCVA (Snellen)

CRT (mm)

Lesion type (classic/occult; %)

Group I (n = 18)

76.9 ± 10.6

17 ± 10

0.45 ± 0.18

429.4 ± 25.9

44.4/39

Group II (n = 18)

80.8 ± 6.7

73 ± 32

0.32 ± 0.15

429.7 ± 87.0

22.2/50

Group III (n = 6)

74.2 ± 8.2

195 ± 10

0.17 ± 0.17

552.8 ± 232.7

0/100

Mean ± standard deviation

BCVA best-corrected visual acuity, CRT central retinal thickness

As to CNV type, the majority of classic CNV was found in group I, 100 % in group III were classified as occult CNV. Minimally classic CNV and occult CNV were concluded in one group. Details are shown in Table 1.

Changes of BCVA from baseline at 2, 6, and 12 months are shown in Table 2 and Fig. 1.

https://static-content.springer.com/image/art%3A10.1007%2Fs00508-012-0249-3/MediaObjects/508_2012_249_Fig1_HTML.gif
Fig. 1

Course of best-corrected visual acuity (BCVA) of all patients (total) and of the three groups regarding the duration of symptoms at baseline, 2, 6 and 12 months

Table 2

Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) of the three groups regarding the duration of symptoms at baseline, 2, 6, and 12 months

 

Group I

Group II

Group III

 

Mean ± SD

p values

95 % Confidence interval (CI)

Range

Mean ± standard deviation, (range)

p values

95 % Confidence interval (CI)

Range

Mean ± standard deviation, (range)

p values

95 % Confidence interval (CI)

Range

Baseline BCVA (Snellen)

0.45 ± 0.18

   

0.32 ± 0.15

   

0.17 ± 0.17

   

BCVA at 2 months

0.55 ± 0.20

0.009a

− 0.16 to − 0.02

 

0.42 ± 0.19

0.01a

− 0.19 to − 0.01

 

0.28 ± 0.33

0.081

− 0.28 to 0.06

 

BCVA at 6 months

0.52 ± 0.19

0.042a

− 0.16 to 0.02

 

0.40 ± 0.19

0.047a

− 0.19 to 0.04

 

0.23 ± 0.26

0.140

− 0.18 to 0.06

 

BCVA at 12 months

0.53 ± 0.23

0.051

− 0.18 to 0.02

 

0.35 ± 0.23

0.246

− 0.16 to 0.09

 

0.23 ± 0.25

0.096

− 0.16 to 0.05

 

Baseline CRT (mm)

429.4 ± 95.9

  

280–616

429.7 ± 87.1

  

205–562

552.8 ± 232.7

  

265–773

CRT at 2 months

360.7 ± 86.6

0.002a

38.3 to 136.2

226–558

308.7 ± 93.2

< 0.001a

64.2 to 158.1

190–631

453.8 ± 145.3

0.317

− 106.5 to 255.4

292–683

CRT at 6 months

359.9 ± 80.1

0.022a

14.1 to 149.5

232–566

308.2 ± 61.2

0.001a

49.2 to 153.8

191–392

426.8 ± 197.1

0.338

− 185.4 to 424.2

296–823

CRT at 12 months

390.4 ± 153.3

0.567

− 77.3 to 135.6

273–903

335.5 ± 75.8

0.009a

22.9 to 134.1

221–463

455.3 ± 165.4

0.573

− 214.2 to 335.4

271–742

BCVA best-corrected visual acuity, SD standard deviation, CRT central retinal thickness

aStatistically significant

Visual gain in group I compared with baseline was statistically significant at the 2 and the 6 months visits. At the 12 months visit, a visual gain was also received, albeit not statistically significant.

Patients in group II also improved visual acuity statistically significant at 2 and 6 months from baseline. Change in visual acuity from baseline to the 12 months visit was not statistically significant.

In group III, stabilization of visual function could be observed, but no statistically significant visual gain.

BCVA improved > 3 lines (15 letters) in 7.5 % and 1–3 lines in 37.5 %; remained within 1 line of baseline in 37.5 %, decreased 1–3 lines in 15 %, and > 3 lines in 7.5 %. Details are shown in Table 3.

Table 3

Gain and loss of best-corrected visual acuity (BCVA) of the three groups regarding the duration of symptoms

Group

> 3 lines improved

1–3 lines improved

± 1 Line of baseline

1–3 lines decreased

> 3 lines decreased

 

Percentage (n)

 

I

5.6 (1)

44.4 (8)

33.3 (6)

11.1 (2)

5.6 (1)

II

11.1 (2)

27.8 (5)

27.8 (5)

22.2 (4)

11.1 (2)

III

0 (0)

33.3 (2)

66.7 (4)

0 (0)

0 (0)

The correlation of visual acuity and duration of symptoms was not only statistically significant at baseline (r = 0.58, p < 0.001), but also after 6 (r = − 0.405, p = 0.008) and 12 (r = − 0.436, p = 0.004) months.

Changes of CRT from baseline at 2, 6, and 12 months are shown in Table 2. Group I and II showed a significant reduction of CRT at all visits, despite the 12 months visit in group I. CRT was also reduced in group III, albeit not significant.

There was no significant correlation of visual acuity and CRT in group I at any visit. In group II, a significant correlation of CRT at baseline and visual acuity at baseline (r = − 0.578, p = 0.030) and after two injections (r = − 0.594, p = 0.025) was found. In group III, a significant correlation of CRT at baseline and visual acuity after 2 and 12 months (r = − 0.900, p = 0.037 and r = − 0.895, p = 0.038, respectively) was detected.

A significant correlation of CRT and number of injection was found at baseline in group I (r = 534, p = 0.049), in group II after 2 and 6 months (r = 0.505, p = 0.033 and r = 0.680, p = 0.003, respectively), and in group III after 12 months (r = 0.833, p = 0.039).

Regarding the duration of symptoms, there was a significant difference concerning lesion type. Patients with classic lesions had a statistically significant shorter duration of symptoms (p = 0.028) and better baseline BCVA (p = 0.059) as shown in Table 4. In patients with classic lesion, there was no statistically significant improvement in BCVA at any time; in patients with occult lesions, it was statistically significant at the 2 and 6 months visits.

Table 4

Change in best-corrected visual acuity (BCVA; Snellen) and duration of symptoms (days) concerning lesion type

 

Classic CNV

Occult CNV

 

Mean ± SD

p values

95 % Confidence interval (CI)

Range

Mean ± standard deviation, (range)

p values

95 % Confidence interval (CI)

Range

BCVA at baseline

0.45 ± 0.20

   

0.30 ± 0.19

   

BCVA at 2 months

0.51 ± 0.20

0.104

− 0.11 to 0.02

 

0.43 ± 0.27

< 0.001a

− 0.19 to − 0.06

 

BCVA at 6 months

0.54 ± 0.18

0.172

− 0.21 to 0.04

 

0.37 ± 0.54

0.045a

− 0.14 to − 0.0

 

BCVA at 12 months

0.50 ± 0.21

0.457

− 0.17 to 0.089

 

0.37 ± 0.59

0.101

− 0.15 to 0.01

 

Duration of symptoms

35 ± 31

  

0–88

88 ± 76

  

0–212

BCVA best-corrected visual acuity, SD standard deviation, CNV choroidal neovascularization

aStatistically significant

Mean number of injections was 4.8 ± 2.0 (median 4.0, range 2–9) during the 12 months follow-up period. No correlation of duration of symptoms and number of injections was found in any group. Patients in group I needed most injections with a mean number of 5.1 ± 2.4.

Discussion

This study showed improvement in BCVA after intravitreal injections of ranibizumab based on an as-needed scheme after two initial injections in all patients with CNV. A longer duration of CNV as measured by the subjective duration of visual symptoms was associated with a worse visual outcome even after 1-year follow-up. Mean duration of symptoms was 66 days, comparable to other studies with a mean time from diagnosis to treatment of 2.3 months [15, 19].

Patients with an estimated duration of less than 6 months showed a statistically significant improvement in BCVA, albeit an improvement of one line is not clinically relevant. Furthermore, patients reporting symptoms more than 6 months resulted in only modest visual increase. Our results confirm to those of Muether et al. [18] and Algvere et al. [21]. These studies also described a significant correlation between months to treatment and visual acuity change. Algvere at al. [21] reported that CNV with shorter disease duration (< 12 months) yielded better visual results after a mean of 4.1 injections per eye at the 6 months’ follow-up than eyes with longstanding CNV (> 12 months). Delay in treatment of more than 28 days resulted in more significant vision loss than early treatment, as investigated by Muether et al. [18]. This presumably might be due to advanced cellular damage to the photoreceptors and subsequent fibrosis of the retinal pigment epithelium (RPE) and subretinal space. The largest increase in BCVA was found after 2 months in all groups, but only patients in group I could preserve their visual gain up to 1 year as shown in Fig. 1. In group II and III, increase in BCVA was lost during follow-up and was similar to the initial BCVA despite several reinjections. These findings are supported by a study conducted by Heimes et al. [23], who investigated the long-term visual course after anti-VEGF therapy.

A considerable decrease of CRT (reduction from 553 mm at baseline to 455 mm at the 12 months visit) without significant improvement of BCVA in group III enforces the assumption that functional outcomes and anatomic outcomes do not necessarily coincide. This implicates that the reinjection strategy should not merely be based on serial OCT scans, but also on the estimated duration of disease.

Concerning lesion type, the majority of classic CNV lesions was found in group I, less in group II, and none in group III, where all patients had occult CNV. This postulates that classic CNV may provoke visual deterioration by penetrating the RPE at an earlier stage than nonclassical lesions. Among eyes with disease duration shorter than 1 month, clinical response following intravitreal injection was particularly good. In some cases, intraretinal edema and subretinal fluid were reabsorbed after only one intravitreal injection. Similar results have been reported by Algvere et al. [21].

Since in our study only patients with occult lesions were presented in all groups, subgroup analyses were performed in these patients concerning possible influence of lesion type. In patients with occult lesions, we found a significant visual gain after two injections in all groups. Patients in group I had the most visual improvements and could maintain this gain during the whole follow-up. In contrast, patients in group II and III returned to baseline visual acuity (VA) after 12 months. This may imply that visual gain is stronger influenced by duration of symptoms than by lesion type.

Mean number of injections was 4.8 in all groups. Patients in group I needed more injections with a mean of 5.1, implicating more activity in classic lesions or tendency to fibrosis and less activity in longstanding CNV. The mean number of injections is similar to those of other studies following an as-needed basis such as the PRONTO study with a mean of 5.6 injections and a recent study conducted by Dadgostar et al. [24] with a mean number of 5.2 injections.

In our study, we found a greater treatment benefit in patients with higher baseline BCVA, as also seen in a subgroup analysis of the MARINA study [13]. Oliver-Fernandez et al. [20] also demonstrated only elapsed time between initial diagnosis and treatment to be associated with the progression of visual loss.

Similar to any study, ours has some limitations, including its retrospective design, small cohort of patients, and a relatively high dropout rate, and therefore does not allow causal inferences. Furthermore, duration of symptoms can only be subjectively assessed and therefore a selection bias cannot be avoided. As another limitation of our study, patients received only doses of two intravitreal injections of ranibizumab, which was common practice at the beginning of the study. In today’s literature, the benefit of an upload with three monthly injections is well described and therefore recommended. Despite the obsolete treatment regimen, all our patients received initially two injections followed by pro re nata, so data of the three groups are comparable in time course. Two initial injections could also be an explanation for poor visual improvement in our study and makes comparison to other study results with a design of three initial injections difficult. However, our results still provide the first specific approach to describe the importance of a short time span between disease onset and initiation of treatment for visual gain over a 1-year period.

In conclusion, this study demonstrates that even short delays in diagnosis of new-onset wet AMD result in persistent loss of BCVA. Results after 1 year are still influenced by deferred start of the initial therapy. In this regard, delays in treating wet AMD should be avoided, in particular the waiting period between diagnosis and treatment should be kept as short as possible. Moreover, the patients’ awareness of visual deterioration should be increased by recommending self-monitoring of the central vision of each eye on a regular basis.

Contributorship statement

Conception and design, or analysis and interpretation of data: Birgit Weingessel, Gregor Hintermayer, Renate Rauch, and Pia Veronika Vecsei-Marlovits.

Drafting the article or revising it critically for important intellectual content: Birgit Weingessel, Gregor Hintermayer, Renate Rauch, Saskia Maca, and Pia Veronika Vecsei-Marlovits.

Final approval of the version to be published: Birgit Weingessel, Renate Rauch, Saskia Maca, and Pia Veronika Vecsei-Marlovits.

Funding statement

This study received a grant from the Novartis Company for a site-initiated trial.

Conflict of interest

The authors have no proprietary interest in any material presented in the study. Pia Veronika Vecsei-Marlovits and Birgit Weingessel received support by the Novartis Company for presentations and consultancy not associated with this study.

Copyright information

© Springer-Verlag Wien 2012