Graefe's Archive for Clinical and Experimental Ophthalmology

, Volume 249, Issue 4, pp 521–527

Patient characteristics and treatment of neovascular age-related macular degeneration in France: the LUEUR1 observational study

Authors

  • Salomon-Yves Cohen
    • Centre Ophtalmologique d’Imagerie et de Laser
  • Eric H. Souied
    • Faculté de Medecine Henri MondorCreteil University Eye Clinic
  • Michel Weber
    • Ophthalmology DepartmentHôtel-Dieu University Hospital
  • Gérard Dupeyron
    • Ophthalmology DepartmentNimes University Hospital
  • Gérard de Pouvourville
    • Health Economics, ESSEC
  • Michel Lievre
    • Clinical Pharmacology DepartmentLyon 1 University, Service de Pharmacologie Clinique, Faculté de Médecine
    • Novartis Pharma SAS
Retinal Disorders

DOI: 10.1007/s00417-010-1553-0

Cite this article as:
Cohen, S., Souied, E.H., Weber, M. et al. Graefes Arch Clin Exp Ophthalmol (2011) 249: 521. doi:10.1007/s00417-010-1553-0

Abstract

Background

Age-related macular degeneration is the primary cause of blindness in developed countries. Current treatments of this degenerative disease mainly include laser, photodynamic therapy with verteporfin and administration of anti-vascular endothelial growth factors. The LUEUR (LUcentis® En Utilisation Réelle) study is composed of a cross-sectional part (LUEUR1), which examined the current management of wet AMD in France, and a follow-up part (LUEUR2), which will assess the development of patients treated for wet AMD over 4 years. Here we describe the results of LUEUR1.

Methods

Patients with wet AMD were enrolled during a routine medical examination in LUEUR1, a cross-sectional, observational, prospective, multicentre study. Investigators recorded patient demographics, visual acuity, characteristics of wet AMD lesions, date of AMD diagnosis, comorbidities, previous treatments, treatments prescribed at inclusion, and low vision rehabilitation.

Results

A total of 72 investigators recruited 1,019 patients with wet AMD, corresponding to 1,405 eyes affected by the disease. The mean age of patients was 78.7 ± 7.3 years. Most were female (62.3%) and non-smokers (66.9%). The mean visual acuity was 49.12 ± 24.18 Early Treatment Diabetic Retinopathy Study letters. Most eyes showed occult (52.8%) and subfoveal (84.6%) choroidal neovascularisation. Bilateral wet AMD affected 37.9% of patients. The median time since diagnosis was 12 months. Ranibizumab-based therapy (67.3%) and photodynamic therapy (29.8%) were the most frequent previous treatments. Prior to inclusion, 5.6% of patients had low vision rehabilitation. When a treatment was prescribed on the day of inclusion, it was most often ranibizumab (89.0% of all treatments at inclusion).

Conclusions

The results of this study illustrate the impact of anti-vascular endothelial growth factor therapies on the treatment of wet AMD in a real-life context. Specifically, ranibizumab-based therapy appears to have largely replaced laser photocoagulation and verteporfin-based photodynamic therapy.

Keywords

NeovascularisationEpidemiologyRetinaAge-related macular degenerationRanibizumabLUEUR

Abbreviations

AMD

age-related macular degeneration

CNV

choroidal neovascularisation

PDT

photodynamic therapy

VEGF

vascular endothelial growth factor

ETDRS

Early Treatment Diabetic Retinopathy Study

Introduction

Age-related macular degeneration (AMD) is the primary cause of blindness in developed countries [1]. Its prevalence worldwide is increasing concomitantly with life expectancy, and epidemiological forecasts estimate that the number of affected patients over 65 years of age will rise up to two-fold by 2030 [2, 3]. In addition to age, well-known risk factors for AMD include smoking and genetic predisposition [47]. The wet (also known as neovascular or exudative) form of this degenerative disease is characterised by the growth of new vessels beneath the macula, leading to the detachment of the retinal pigmented epithelium and the neurosensory retina and, therefore, to a severe loss of central vision [4].

Verteporfin (Visudyne®, Novartis) was the first approved drug for wet AMD in Europe, with marketing authorization granted in 2000. It is administered intravenously during photodynamic therapy (PDT) and, when activated by laser irradiation in the area of the retinal lesion, causes the photochemical oxidation of the vascular endothelium, halting the growth of new vessels [3]. A major advance in the treatment of wet AMD occurred a few years later, with the development of molecules that inhibit the physiological effects of vascular endothelial growth factor (VEGF), a key regulator of angiogenesis and vascular permeability [8]. Since then, anti-VEGF intravitreal injections have become the first choice in the treatment of wet AMD [9]. Pegaptanib (Macugen®, Pfizer), which received marketing authorization in 2006, is a ribonucleic acid aptamer, administered by intravitreal injection, that blocks the production of VEGF isoform 165 [3]. Ranibizumab (Lucentis®, Novartis), an intravitreal drug approved for use in 2007, is a recombinant Fab fragment of a monoclonal antibody with high affinity for all VEGF isoforms [3]. Pivotal trials investigating the efficacy of ranibizumab (MARINA and ANCHOR) have demonstrated that intravitreal injections of this drug improve visual acuity in 33% to 40% of patients, whereas pegaptanib only slows progression of the disease [10, 11]. Finally, although developed and approved for intravenous use in the treatment of colorectal and lung cancer, bevacizumab (Avastin®, Roche), a full-length recombinant monoclonal antibody against VEGF, is used off-label to treat wet AMD [3, 12].

Following marketing approval for ranibizumab, the French Health Authority (Haute Autorité de Santé) has requested an observational study to assess the real-life use and impact of ranibizumab in the treatment of wet AMD. The LUEUR (LUcentis® En Utilisation Réelle) study was designed to fulfil this request. The study is composed of a cross-sectional part (LUEUR1), which examined the current management of wet AMD in France, and a follow-up part (LUEUR2), which will assess the development of patients treated for wet AMD over 4 years. Here, we describe the results of LUEUR1.

Materials and methods

Study design

The first part of the LUEUR study (LUEUR1), described here, was an observational, cross-sectional, prospective, multicenter study on the management of wet AMD in metropolitan France. This study, carried out between July 2008 and June 2009, characterized patients with wet AMD, their previous and current treatments, and their lesion characteristics. The study was approved by the Data Protection Advisory Committee and the National Commission on Informatics and Freedom, and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. All participants in the study provided written informed consent.

Investigator and patient enrolment

Investigators were randomly selected from a list of hospital- or office-based ophthalmologists caring for patients with wet AMD in metropolitan France. To ensure the participation of 500 patients in the follow-up part of the study (LUEUR2), an estimated 1,020 patients were needed in LUEUR1. From July 2008 to May 2009, each participating investigator recruited ten to 40 consecutive patients who were suffering from wet AMD and who consented to participate in the study and allow access to their medical data. Patients were excluded if they were participating in an ophthalmologic clinical trial.

Evaluations

The status of each participating investigator, specifically whether they were in the private or public sector, was recorded. Patient data were collected at the inclusion visit, which took place during a routine medical examination. Patient data included patient demographics, visual acuity, characteristics of wet AMD lesions, date of AMD diagnosis, comorbidities, previous treatments, treatments prescribed at inclusion, and low vision rehabilitation. In addition, the investigators were asked to answer yes or no to the question “Did the visual impairment of the patient result in a loss of autonomy (help needed for daily activities, moving to an institution)?” Visual acuity was measured using the Monoyer or the Snellen chart (at a distance of 20 feet). These values were converted into Early Treatment Diabetic Retinopathy Study (ETDRS) scores according to the conversion rules of Zanlonghi et al. [13]. Size, type (classic, occult, or mixed), and location (extra-, juxta-, or sub-foveal) of choroidal neovascularization (CNV), together with the associated lesions and ocular comorbidities, were assessed by the investigator according to their clinical practice and without specific guidance.

Statistical analysis

Analyses were carried out on a per-eye and per-patient basis. Student’s t-test was used to detect differences between means, and a chi-squared test was used to examine associations between categorical variables. All analyses were performed using SAS, version 9.1.3 (SAS Institute, Inc., Cary, NC, USA). Missing data were not taken into account for the calculation of percentages.

Results

Patient and AMD characteristics

A total of 72 investigators recruited 1,019 patients with wet AMD, corresponding to 1,405 eyes affected by the disease. Among the investigators, 36% were working in public hospitals and 64% in private clinics or surgeries. The median number of patients recruited per centre was ten. The mean age of patients was 78.7 ± 7.3 years. Most were female (62.3%) and non-smokers (66.9%). The mean visual acuity of the 1,405 wet AMD eyes was 49.12 ± 24.18 ETDRS letters (Table 1). Most eyes showed occult (52.8%) and subfoveal (84.6%) CNV. The most common type of ocular comorbidity was extensive non-operated cataract, which was diagnosed in 8.3% of the eyes. Bilateral AMD affected 37.9% of patients. Of these, 5.2% had a visual acuity ≤1/10 according to the Monoyer chart or to 35 letters according to the EDTRS scale.
Table 1

Characteristics of the eyes with AMD

Characteristics of eyes with AMD

Value

VA (ETDRS letters) (n = 1,387)

 Mean ± SD

49.12 ± 24.18

 Median

55.00

 Range

[1.00–90.00]

Size of lesion (disk diameter) (n = 1,361)

 Mean ± SD

2.08 ± 1.92

 Median

1.50

 Range

[0.00–20.50]

CNV type, n (%)

 Classic only

560 (40.7)

 Occult only

727 (52.8)

 Mixed

89 (6.5)

Location of CNV, n (%)

 Subfoveal

1180 (84.6)

 Juxtafoveal

184 (13.2)

 Extrafoveal

31 (2.2)

Associated lesion, n (%)

 Fibrosis

424 (30.5)

 Haematoma

167 (12.0)

Ocular comorbidities, n (%)

 Diabetic maculopathy

4 (0.3)

 Glaucoma with central vision loss

3 (0.2)

 Extensive non-operated cataract

116 (8.3)

n = number of eyes for which results were available; VA = visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study; SD = standard deviation; CNV = choroidal neovascularisation.

The mean time since diagnosis for all patients was 22 ± 30 months, with a median of 12 months (Table 2). The median time since diagnosis was shorter for patients with unilateral wet AMD than for patients with bilateral wet AMD (8 vs 24 months; p < 0.0001). The mean time between diagnoses of both eyes for patients with bilateral AMD was 17 ± 33 months, with a median of 2 months. The time since diagnosis per eye was also significantly different depending on the previous administered treatments (p < 0.0001). Finally, there was a negative correlation between time since diagnosis and visual acuity (p < 0.0001; Fig. 1).
Table 2

Time since diagnosis

 

Time since diagnosis (months)

Median

Range

All patients with wet AMD (n = 1,001)

12

[0–403]

Laterality of wet AMD

 Patients with unilateral AMD (n = 629)

8

[0–170]

 Patients with bilateral AMD (n = 381)

24

[0–403]

Previous treatments

 Eyes with no previous treatment for wet AMD (n = 228)

1

[0–122]

 Eyes with previous ranibizumab treatment only (n = 597)

7

[0–277]

 Eyes with previous ranibizumab and other treatments (n = 338)

23

[1–160]

 Eyes with previous treatments for wet AMD which were not ranibizumab (n = 209)

34

[0–403]

AMD = age-related macular degeneration, n = number of available results for each parameter.

https://static-content.springer.com/image/art%3A10.1007%2Fs00417-010-1553-0/MediaObjects/417_2010_1553_Fig1_HTML.gif
Fig. 1

Time since diagnosis as a function of visual acuity (n = 1,355 eyes; p < 0.0001 for multiple comparison between categorical means)

Treatments of wet AMD

At inclusion, 1,164 diseased eyes (83.1%) had been previously treated for wet AMD (Fig. 2). Of these, 53.8% were previously treated with one treatment, 21.2% with two different treatments, and 6% with three. Anti-VEGF therapy was the most frequent type of previous treatment, with 67.3% of the eyes treated with ranibizumab, 8% with bevacizumab, and 4.4% with pegaptanib (Table 3). PDT was the second-most frequently used treatment (29.8%). For patients with bilateral wet AMD, the nature of the previous treatment in one eye did not correlate with the nature of the previous treatment in the other eye (p > 0.05; data not shown). A total of 237 eyes (16.9%) had never been treated for wet AMD prior to inclusion into the study (Fig. 2). Of these, 100 (7.1% of all eyes, or 42.2% of the eyes not previously treated) did not receive any treatment during the inclusion visit. Among the 137 eyes that were treated for the first time on the day of inclusion, 128 (93.0%) were prescribed ranibizumab.
https://static-content.springer.com/image/art%3A10.1007%2Fs00417-010-1553-0/MediaObjects/417_2010_1553_Fig2_HTML.gif
Fig. 2

Distribution of diseased eyes according to treatments for wet AMD

Table 3

Nature of the treatments administered to eyes with wet AMD

 

Previous treatments: n (%)

Treatments prescribed at inclusion visit: n (%)

Laser

92 (6.6)

2 (0.1)

PDT with verteporfin

418 (29.8)

32 (2.3)

Bevacizumab

112 (8.0)

30 (2.1)

Ranibizumab

944 (67.3)

649 (46.3)

Pegaptanib

61 (4.4)

9 (0.6)

Intravitreal corticosteroids

80 (5.7)

1 (0.1)

Surgery

8 (0.6)

3 (0.2)

Transpupillary thermotherapy

3 (0.2)

0 (0.0)

Other treatments

5 (0.4)

3 (0.2)

None

237 (16.9)

696 (49.6)

PDT = photodynamic therapy, n (%) = number of treated eyes and corresponding percentage based on 1,405 eyes.

Regardless of whether the diseased eyes were previously treated, when a treatment was prescribed on the day of inclusion, it was most often ranibizumab (46.3% of all eyes, corresponding to 89.0% of all treatments at inclusion; Table 3). Few eyes received PDT with verteporfin (2.3%), bevacizumab (2.1%), or pegaptanib (0.6%). One eye (0.1%) was prescribed two anti-VEGF based treatments, 19 (1.4%) were prescribed anti-VEGF and PDT, one (0.1%) was prescribed anti-VEGF and corticosteroids, and none received other treatment combinations. The prescription of ranibizumab was higher in the group of eyes without previous treatment than in the group of pre-treated eyes (54.0% vs 44.8%; Table 4). In addition, among the 521 pre-treated eyes prescribed with ranibizumab during the inclusion visit, 490 (42.1%) were already treated with ranibizumab before the study (alone or in combination with other treatments). With regard to the 28 eyes prescribed with bevacizumab at the inclusion visit, 13 were previously treated with ranibizumab (alone or in combination with other treatments).
Table 4

Nature of the treatments prescribed at inclusion visit for the eyes with or without previous treatment for wet AMD

Treatments at inclusion visit

Eyes with previous treatments: n (%)

Eyes with no previous treatment: n (%)

Totals

1,164 (100)

237 (100)

Laser

1 (0.1)

1 (0.4)

PDT with verteporfin

20 (1.7)

12 (5.1)

Bevacizumab

28 (2.4)

2 (0.8)

Ranibizumab

521 (44.8)

128 (54.0)

Pegaptanib

9 (0.8)

0 (0.0)

Intravitreal corticosteroids

1 (0.1)

0 (0.0)

Surgery

3 (0.3)

0 (0.0)

Transpupillary thermotherapy

0 (0.0)

0 (0.0)

Other treatments

3 (0.3)

0 (0.0)

None

596 (51.2)

100 (42.2)

PDT = photodynamic therapy, n (%) = number of treated eyes and corresponding percentage.

Prior to inclusion, 11.4% of the patients had a low-vision examination, 5.6% had undergone low-vision rehabilitation, and 17.2% had bought visual aids. Finally, the investigators reported a loss of autonomy due to AMD for 10% of the patients.

Discussion

This observational study, carried out in a real-life clinical setting, examined the management of wet AMD in France between July 2008 and May 2009, 1 year after introduction of anti-VEGF therapies. We found that most eyes diagnosed with wet AMD had occult and subfoveal CNV, that more than one third of patients had bilateral AMD, and that most patients were treated with ranibizumab prior to or during the day of the inclusion in the study.

This study was intended to reflect the variety of wet AMD cases seen by ophthalmologists in daily clinical practice. Therefore, all patients with wet AMD were included, regardless of their disease severity, treatment history, or time since diagnosis. Patient characteristics (age and sex-ratio) and visual acuity data were consistent with the findings from other observational studies carried out in Europe during the early 2000s [10, 11, 14, 15]. Furthermore, the proportion of each CNV location was similar to pooled results of international studies [16]. It should be noted that a substantial proportion of the eyes without previous treatment for wet AMD did not receive any treatment during the inclusion visit (42.2%). Because most of the eyes without previous treatments were recently diagnosed (median time since diagnosis = 1 month), the absence of prescribed therapy at the inclusion visit might be explained by a diagnosis of early AMD lesions with preserved vision, for which a treatment might have been deemed useless. Regarding the 596 eyes previously treated for wet AMD but for which a treatment was not administered at inclusion, it is possible that the inclusion visit took place during a monitoring visit.

In 2003, a French observational study including 105 patients with wet AMD showed that 72.4% of the patients had been previously treated by laser [17]. In the present study, although the mean period since diagnosis was half as long (22 ± 31 months vs 44 ± 40 months), laser treatment was previously administered to 6.6% of the eyes, corresponding to only 8.4% of the patients. In 2004, a marked decrease in the prescription of laser treatment (from 7.1% to 3.9% of all patients with CNV) was already reported in an Austrian study, as a consequence of the introduction of PDT with verteporfin 2 years before [18]. A French prospective case series in 2005 recorded the treatments prescribed at the inclusion visit for 207 patients with newly diagnosed wet AMD [19]. In that study, ophthalmologists prescribed PDT in 47.8% of the cases, laser in 15.5%, intravitreal corticosteroids in 4.3%, a combination of treatments in 15%, and other treatments in 2.4%. Although a recent wet AMD diagnosis was not required for the recruitment of patients in LUEUR1, the differences in the frequency of each prescribed treatment at inclusion (PDT for 2.3% of the eyes, laser for 0.1%, intravitreal corticosteroids for 0.1%, anti-VEGF for 49.4%, and a combination of treatments for 1.5%) suggest that during the last decade, anti-VEGF therapies have largely replaced laser photocoagulation and verteporfin-based PDT. This is confirmed by the fact that in LUEUR1, 93% of the patients who started a treatment at the inclusion visit were prescribed ranibizumab.

Since the 1990s, studies following patients with unilateral AMD have helped clarify how and when CNV develops in the fellow eye [16, 20, 21]. In the present study, more than one third (37.9%) of patients suffered from bilateral wet AMD, which was less than previously reported [22, 23]. This may reflect ophthalmologists’ awareness of the high risk for developing CNV in the fellow eye during advanced stages of the disease. In addition, the development of optical coherence tomography techniques, which allow non-invasive cross-sectional imaging of the retina, may have improved the prevention of wet AMD in the second eye [24, 25].

Although the percentage of occult only CNV was consistent with previous studies, the percentage of classic CNV without an occult component appeared higher [7, 19]. In addition, haematoma was reported in more patients than expected, possibly due to confusion with subretinal haemorrhage, which is frequently associated with CNV [26]. These differences may arise from the lack of data review by independent experts. In fact, previous studies have shown that agreement among ophthalmologists on the type and size of CNV is variable, with local ophthalmologists more frequently classifying lesions as "'classic only" than independent ophthalmologists [19, 24]. In this study, the classification of the CNV was based on the data reported by French physicians. The lack of a reading centre for classification of the phenotype could be a limitation of this study.

As in any clinical study, the results should be interpreted in light of a possible self-selection bias in the recruitment of investigators. This was also the case for enrolment of the patients, because informed consent was required to participate in this study. In addition, the time since diagnosis was an important confounding factor for several reasons. First, not all treatments were available at the same moment. For example, in France, laser-based treatments have been available since the 1970s, whereas PDT and anti-VEGFs have been used since 2000 and 2006 respectively. Second, an increased time since diagnosis resulted in an increased severity of AMD symptoms because the natural progression of the disease leads to losses in visual acuity, CNV development in the fellow eye, subfoveal CNV location, and fibrosis. Due to the cross-sectional nature of the study, we could not assess to what extent the time since diagnosis influenced the characteristics of AMD lesions and the prescribed treatments; therefore, we could not establish a causal relationship between these parameters.

In conclusion, the demographic characteristics of patients with wet AMD in this study were consistent with those reported in previous European studies. Although the results need to be interpreted in the context of a cross-sectional study, we found intensive use of ranibizumab in real-life clinical practice, suggesting that ophthalmologists currently consider anti-VEGF drugs effective for treating wet AMD.

Acknowledgments

We thank the physicians who kindly participated in this study. The study was conducted by EZUS, University of Lyon, France for Novartis Pharma and by the study scientific committee (SY Cohen, G De Pouvourville, G Dupeyron, M Lievre, E Souied and M Weber). All members of the scientific committee had a direct role in study design, analysis and interpretation of data as well as in the writing of and decision to submit this manuscript. We also thank 4Clinics (Waterloo, Belgium) for assistance in writing this manuscript.

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© Springer-Verlag 2010