Intravitreal Anti-Vascular Endothelial Growth Factor Drugs for Retinal Angiomatous Proliferation in Real-Life Practice

Abstract

Purpose:

To describe the outcomes of intravitreal anti-vascular endothelial growth factor (VEGF) in the treatment of retinal angiomatous proliferation (RAP) in real-life practice in 7 Italian centers under the Progetto Luce initiative.

Methods:

Clinical data of 95 eyes of 95 patients affected by RAP, regularly followed up and treated with either intravitreal ranibizumab or bevacizumab over 12 months, were examined. After a loading phase of 3 consecutive injections, retreatments were administered following a pro-re-nata regimen on the basis of the persistence or the recurrence of subretinal/intraretinal fluid on optical coherence tomography, or leakage on fluorescein angiography.

Results:

Overall, the mean best corrected visual acuity changed from 0.66 to 0.53 LogMAR (P: 0.0003); 36.8% of eyes gained at least 3 ETDRS lines, whereas 13.7% lost >3 lines at the end of the follow-up. Mean central retinal thickness improved from 384 μm at baseline to 262 μm at the 12-month examination (P < 0.001). A serous pigment epithelium detachment (PED) was identified in 68.4% of eyes at baseline, and it was still detectable in 30.5% at the end of follow-up. The mean number of injections was 4.4 over the follow-up. A significantly greater proportion of eyes showed PED resolution in the subgroup treated with ranibizumab (P < 0.001).

Conclusions:

Intravitreal anti-VEGF treatment in routine clinical practice allows a significant improvement in visual function in patients affected by RAP. A limited number of anti-VEGF injections are generally required in most cases.

Introduction

Retinal angiomatous proliferation (RAP) is a variant of age-related macular degeneration (AMD) characterized by retinal neovascularization or chorioretinal anastomosis.^1–4 RAP has been recently defined as neovascularization type 3, according to the new classification of neovascularizations.² RAP pathogenesis is still controversial, one theory hypothesizing that the neovascular process has its origin in the retina, with later choroidal involvement,¹ whereas another theory suggesting that the new vessels might develop in the choroid as occult neovascularization, to later expand into the retina.³ Although the initial origin of the lesion is uncertain, the neovascular complex shows a high vasogenic potential and the natural course leads to poor visual outcomes, with frequent bilateral involvement.^2–5 To halt the visual acuity deterioration, a variety of treatments have been tried, including laser photocoagulation,^5–8 transpupillary thermotherapy,⁵ surgical removal,^9,10 and photodynamic therapy alone^11–14 or combined with intravitreal triamcinolone acetonide.^15–18 Nevertheless, no approach has been shown to be completely effective to guarantee a significant visual acuity improvement over the follow-up. Conversely, the recent introduction of the intravitreal anti-vascular endothelial growth factor (VEGF) molecules in the management of RAP has shown good potential, ensuring a remarkable improvement in visual acuity in a high proportion of patients.^19–24 However, no study has specifically evaluated the effects of an anti-VEGF approach for RAP in a real-life clinical practice.

The aim of the present study is to analyze the management of patients with RAP receiving anti-VEGF treatment in routine clinical practice in 7 Italian clinical centers.

Methods

The design of the study was a retrospective, interventional multicenter study conducted in 7 Italian centers of Lombardy, under the Progetto Luce initiative.

Patients affected by RAP, who underwent intravitreal anti-VEGF between June 2012 and January 2014, were considered. Written consent from each patient before inclusion and approval from the institutional review boards were obtained. Inclusion criteria were as follows: diagnosis of RAP achieved by means of fluorescein angiography (FA), indocyanine green angiography (ICGA), and spectral-domain optical coherence tomography (SD-OCT); best corrected visual acuity (BCVA) of at least 20/400; follow-up of at least 12 months; and intravitreal treatment with either ranibizumab or bevacizumab. All charts of the included patients must comply with these parameters: presence of a complete ophthalmologic examination, including BCVA on Early Treatment Diabetic Retinopathy Study charts, FA, ICGA, and SD-OCT at baseline. Exclusion criteria were as follows: any previous treatment for RAP (laser photocoagulation, submacular surgery, and photodynamic therapy); complications due to the neovascularization process, such as rips in the retinal pigment epithelium (RPE), RPE atrophy, and scarring; and presence of any other macular or optic nerve disease. The treatments were performed using intravitreal injections either of ranibizumab (Lucentis; Novartis Pharma, Switzerland) or bevacizumab (Avastin; Roche, Switzerland). Bevacizumab was fractioned by each hospital pharmacy, according to the guidelines of Italian Society of Ophthalmology. The treatment protocol included a loading phase of 3 consecutive injections, with further retreatments following a pro-re-nata regimen on the basis of the identification of persistence or recurrence of subretinal/intraretinal fluid on SD-OCT, and leakage on FA. Each patient underwent a monthly examination complete of BCVA measurement, biomicroscopic examination, and SD-OCT scan. FA and ICGA had to be carried out every 3 months. Furthermore, each investigator could perform additional FA and ICGA at any time over the follow-up to clarify uncertain cases.

The study complied with the tenets of the Declaration of Helsinki.

The main outcome measure was the change in the mean BCVA at 12 months. Secondary outcomes included changes in the mean central retinal thickness (CRT) and number of injections over the 12-month follow-up.

Results

Overall, clinical data of 95 eyes of 95 patients were analyzed. Mean ± standard deviation age was 62 ± 19 years, with 53 males and 42 females. Complete clinical data are listed in Table 1. No bilateral cases were included. All patients completed the 12-month follow-up.

Table 1.

Complete Clinical Data of 95 Eyes Affected by Retinal Angiomatous Proliferation and Treated with Anti-Vascular Endothelial Growth Factor over 12-Month Follow-Up

	Baseline BCVA	Final BCVA	Baseline CRT	Final CRT	Baseline PED	Final PED	Number of injections
Overall patients (95)	0.66 ± 0.28	0.53 ± 0.32 (P < 0.01)	384 ± 137	262 ± 112 (P < 0.01)	65 (68.4%)	29 (30.5%)	4.4 ± 1.2
Ranibizumab patients (69)	0.65 ± 0.28	0.51 ± 0.33 (P < 0.05)	414 ± 146	279 ± 127 (P < 0.01)	47 (68.1%)	19 (27.5%)	4.3 ± 1.1
Bevacizumab patients (26)	0.68 ± 0.28	0.57 ± 0.27 (P < 0.01)	309 ± 69	220 ± 39 (P < 0.01)	18 (69.2%)	10 (38.5%)	4.6 ± 1.6

A statistically significant improvement in visual acuity and central retinal thickness was recorded in all subgroups. A statistically significant difference was found comparing data of eyes showing resolution of pigment epithelium detachment at the 12-month examination, favoring treatment with ranibizumab (P < 0.001).

BCVA, best corrected visual acuity; CRT, central retinal thickness; PED, pigment epithelium detachment.

The mean BCVA changed from 0.66 ± 0.28 LogMAR to 0.53 ± 0.32 LogMAR (P: 0.0003) at the end of the 12-month follow-up. Thirty-five eyes (36.8%) gained at least 3 ETDRS lines, whereas 13 eyes (13.7%) lost >3 lines. Examining in more detail the 13 patients who lost >3 lines, 8 eyes showed the development of subretinal fibrosis and 7 eyes disclosed atrophic changes at the end of the follow-up (Fig. 1).

FIG. 1.

Example of RAP lesion: (a) baseline and (b) 12-month follow-up after anti-VEGF treatment. (clockwise order from upper left: infrared imaging, fluorescein angiography, indocyanine angiography, and OCT imaging). OCT, optical coherence tomography; RAP, retinal angiomatous proliferation; VEGF, vascular endothelial growth factor.

The mean CRT improved from 384 ± 137 to 262 ± 112 μm (P < 0.01).

The morphological assessment of the treated lesions revealed that 10 eyes presented a RAP stage 1 (10.7%), 17 eyes a RAP stage 2 (17.8%), and 68 eyes a RAP stage 3 (71.5%).

Sixty-five eyes (68.1%) showed serous pigment epithelium detachment (PED) at baseline, which was still visible in 29 eyes (30.5%) at the end of the follow-up (Table 2).

Table 2.

Clinical Characteristics of the Lesions at Baseline and 12-Month Follow-Up

	Type of RAP
	RAP stage 1	RAP stage 2	RAP stage 3
Overall patients	10 (10.7)	17 (17.8)	68 (71.5)
Ranibizumab patients (69)	7 (10.1)	13 (18.8)	50 (72.4)
Bevacizumab patients (26)	3 (11.5)	4 (15.3)	18 (69.2)

	At baseline				At month 12
	PED	IRF	SRF	FA leakage	PED	IRF	SRF	FA leakage
Overall patients	65 (68.4)	94 (98.9)	76 (78)	95 (100)	29 (30.5)	28 (29.4)	13 (13.6)	29 (30.5)
Ranibizumab patients (69)	47 (68.1)	68 (98.5)	54 (78.2)	69 (100)	19 (27.5)	20 (28.9)	10 (14.4)	21 (30.4)
Bevacizumab patients (26)	18 (69.2)	26 (100)	22 (84.6)	26 (100)	10 (38.5)	8 (30.7)	3 (11.5)	8 (30.7)

FA, fluorescein angiography; IRF, intraretinal fluid; RAP, retinal angiomatous proliferation; SRF, subretinal fluid.

Each patient received a mean of 4.4 ± 1.2 injections within the 12-month follow-up.

Examination of patient distribution regarding the drug administered over the follow-up revealed that 26 patients (27.3%) received bevacizumab, whereas 69 (72.6%) patients were treated with ranibizumab. All the eyes were treated using the same drug over the whole follow-up.

A statistically significant improvement both in mean visual acuity and in CRT was registered in both subgroups at the end of the follow-up (Table 1). No difference was found between the 2 subgroups regarding the number of injections, but a statistically significant difference was registered comparing the rate of resolution of PED at the 12-month examination, where ranibizumab appeared more effective than bevacizumab (P < 0.05).

No ocular or systemic side effects were registered over the 12-month follow-up.

Discussion

The anti-VEGF approach has greatly improved the treatment outcomes in eyes affected by exudative neovascular AMD. In particular, both the morphological and the functional effects of anti-VEGF treatment of RAP generally provide better results in comparison to the other subtypes of AMD-related neovascularizations. The results obtained from several prospective clinical trials have shown that a remarkable improvement in visual acuity could be achieved in a large proportion of patients, both in short- and long-term follow-up. In addition, the mean number of injections over the first year was relatively low, ranging from 3.9 to 6.1.^19–24

Nevertheless, the actual translation from clinical trials to real-life clinical practice is often hard, generally resulting in a more limited visual acuity gain, mainly related to a lower number of anti-VEGF injections.^25–31

Our retrospective study on the real-life anti-VEGF treatment of RAP involving 7 Italian centers demonstrates that results comparable to those obtained in the clinical trials can also be achieved in routine clinical practice.

It is remarkable that the mean number of anti-VEGF injections registered in our study corresponds to 4.4. This finding is perfectly in line with that already shown by previous studies.^19–24,32 Indeed, most of the real-life studies regarding anti-VEGF management of AMD reported that the mean number of injection in the first year lies between 4 and 5. Thus, the common real-life management leading to an apparently low number of injections may turn out to be enough for the practical management of RAP lesions. A clinical trial extending the follow-up to the 3 years indicated that 10.2 injections were required overall, suggesting that RAP could necessitate fewer injections compared to the other neovascular AMD subforms.³² A recent CATT report showed that at both 1 and 2 years after initiation of anti-VEGF treatment in eyes with RAP received a lower mean number of injections in year 1 and 2 with respect to eyes without RAP, with a similar functional improvement.¹⁹

Comparing the outcomes of the 2 molecules used in our retrospective study, the results appeared to be quite similar for BCVA gain, CRT, and number of injections. The marginal superiority of ranibizumab especially regarding the flattening of PED has already been highlighted by another trial.²² This response could be ascribed to the deeper penetration of the ranibizumab molecule, allowing a powerful effect in drying the fluid, as also shown by the CATT and IVAN trials.^19,33,34

It is not surprising that almost 3 quarters of the patients in our case series received ranibizumab injections, due to the regulations in Italy, where ranibizumab was approved and specifically reimbursed for AMD. The administration of bevacizumab was allowed only in some departments when economical issues were stringent.

We acknowledge that the present study has some limitations. First, the retrospective evaluation of patients' charts could be a source of bias, as well as the multicenter nature of the study. We decided to include just patients who fully completed 12-month follow-up with complete adherence to the visit protocol, but we cannot rule out possible discrepancies in the treatment assessment among the centers. Second, 2 different molecules were used in the centers according to the local availability. Thus, while this condition perfectly reflects the current practical situation, the specific choice could have affected the outcomes. In addition, there was no central reading center, allowing the retreatment to be decided on the basis of the local center discretion.

In conclusion, our data indicate that anti-VEGF management of RAP can also provide good clinical results in routine clinical practice. A mean number of 4.5 anti-VEGF injections can ensure a good clinical stabilization in most patients affected by RAP. Further clinical-practice studies are needed to assess the effects of anti-VEGF molecules for each specific AMD subform.

Footnotes

Author Disclosure statement

No competing financial interests exist.

References

Yannuzzi

L.A.

, Negrao

, Lida

, et al. Retinal angiomatous proliferation in age-related macular degeneration. Retina. 21:416–434, 2001.

Freund

K.B.

, Zweifel

S.A.

, and Engelbert

Do we need a new classification for choroidal neovascularization in age-related macular degeneration?. Retina. 30:1333–1349, 2010.

Gass

J.D.

, Agarwal

, Lavina

A.M.

, and Tawansy

K.A.

Focal inner retinal hemorrhages in patients with drusen: an early sign of occult choroidal neovascularization and chorioretinal anastomosis. Retina. 23:741–751, 2003.

Hartnett

M.E.

, Weiter

J.J.

, Staurenghi

, et al. Deep retinal vascular anomalous complexes in advanced age-related macular degeneration. Ophthalmology. 103:2042–2053, 1996.

Bottoni

, Massacesi

, Cigada

, et al. Treatment of retinal angiomatous proliferation in age-related macular degeneration: a series of 104 cases of retinal angiomatous proliferation. Arch. Ophthalmol., 123:1644–1650, 2005.

Bressler

N.M.

Retinal anastomosis to choroidal neovascularization: a bum rap for a difficult disease. Arch. Ophthalmol., 123:1741–1743, 2005.

Slakter

J.S.

, Yannuzzi

L.A.

, Schneider

, et al. Retinal choroidal anastomoses and occult choroidal neovascularization in age-related macular degeneration, Ophthalmology. 107:742–753, 2000.

Johnson

T.M.

, and Glaser

B.M.

Focal laser ablation of retinal angiomatous proliferation. Retina. 26:765–772, 2006.

Sakimoto

, Gomi

, Sakaguchi

, and Tano

Recurrent retinal angiomatous proliferation after surgical ablation. Am. J. Ophthalmol., 139:917–918, 2005.

10.

Shiragami

, Iida

, Nagayama

, et al. Recurrence after surgical ablation for retinal angiomatous proliferation. Retina. 27:198–203, 2007.

11.

Boscia

, Furino

, Sborgia

, et al. Photodynamic therapy for retinal angiomatous proliferations and pigment epithelium detachment. Am. J. Ophthalmol., 138:1077–1079, 2004.

12.

Silva

R.M.

, Faria de Abreu

J.R.

, Travassos

, and Cunha-Vaz

J.G.

Stabilization of visual acuity with photodynamic therapy in eyes with chorioretinal anastomoses. Graefes Arch. Clin. Exp. Ophthalmol., 242:368–376, 2004.

13.

Boscia

, Battaglia Parodi

, Furino

, et al. Photodynamic therapy with verteporfin for retinal angiomatous proliferation. Graefes Arch. Clin. Exp. Ophthalmol., 244:1224–1232, 2006.

14.

Panagiotidis

, Karagiannis

D.A.

, and Baltatzis

Photodynamic therapy in retinal angiomatous proliferation stage I. Eur. J. Ophthalmol., 16:326–329, 2006.

15.

Freund

K.B.

, Klais

C.M.

, Eandi

C.M.

, et al. Sequenced combined intravitreal triamcinolone and indocyanine green angiography-guided photodynamic therapy for retinal angiomatous proliferation. Arch. Ophthalmol., 124:487–492, 2006.

16.

Van de Moere

, Kak

, Sandhu

S.S.

, and Talks

S.J.

Anatomical and visual outcome of retinal angiomatous proliferation treated with photodynamic therapy and intravitreal triamcinolone. Am. J. Ophthalmol., 143:701–704, 2007.

17.

Krebs

, Krepler

, Stolba

, et al. Retinal angiomatous proliferation: combined therapy of intravitreal triamcinolone acetonide and PDT versus PDT alone. Graefes Arch. Clin. Exp. Ophthalmol., 246:237–243, 2008.

18.

Spaide

R.F.

, Sorenson

, and Maranan

Photodynamic therapy with verteporfin combined with intravitreal injection of triamcinolone acetonide for choroidal neovascularization. Ophthalmology. 112:301–304, 2005.

19.

Daniel

, Shaffer

, Ying

G.S.

, et al. Outcomes in eyes with retinal angiomatous proliferation in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). Ophthalmology. 123:609–616, 2016.

20.

Gharbiya

, Allievi

, Recupero

, et al. Intravitreal bevacizumab as primary treatment for retinal angiomatous proliferation: twelve-month results. Retina. 29:740–749, 2009.

21.

Atmani

, Voigt

, Le Tien

, et al. Ranibizumab for retinal angiomatous proliferation in age-related macular degeneration. Eye. 24:1193–1198, 2010.

22.

Battaglia Parodi

, Iacono

, Menchini

, et al. Intravitreal bevacizumab versus ranibizumab for the treatment of retinal angiomatous proliferation. Acta Ophthalmol. 91:267–273, 2013.

23.

Seidel

, Werner

, Weger

, et al. Combination treatment of photodynamic therapy with verteporfin and intravitreal ranibizumab in patients with retinal angiomatous proliferation. Acta Ophthalmol. 91:e482–e485, 2013.

24.

Shin

J.Y.

, and Yu

H.G.

Optical coherence tomography-based ranibizumab monotherapy for retinal angiomatous proliferation in Korean patients. Retina. 34:2359–2366, 2014.

25.

Holz

F.G.

, Tadayoni

, Beatty

, et al. Multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration. Br. J. Ophthalmol., 99:220–226, 2014.

26.

Cohen

S.Y.

, Mimoun

, Oubraham

, et al. Changes in visual acuity in patients with wet age-related macular degeneration treated with intravitreal ranibizumab in daily clinical practice: the LUMIERE Study. Retina. 33:474–481, 2013.

27.

Cohen

S.Y.

, Dubois

, Tadayoni

, et al. Results of one-year's treatment with ranibizumab for exudative age-related macular degeneration in a clinical setting. Am. J. Ophthalmol., 148:409–413, 2009.

28.

Finger

R.P.

, Wiedemann

, Blumhagen

, et al. Treatment patterns, visual acuity and quality-of-life outcomes of the WAVE study—a noninterventional study of ranibizumab treatment for neovascular age-related macular degeneration in Germany. Acta Ophthalmol., 91:540–546, 2013.

29.

Finger

R.P.

, and Holz

F.G.

Access to healthcare services for elderly patients with neovascular age-related macular degeneration. Ophthalmologe. 109:474–478, 2012.

30.

Rotsos

, Patel

P.J.

, Chen

F.K.

, et al. Initial clinical experience of ranibizumab therapy for neovascular age-related macular degeneration. Clin. Ophthalmol., 4:1271–1275, 2010.

31.

Pece

, Azzolini

, Parodi

M.B.

, et al. Consensus on the diagnosis, treatment and follow-up of patients with age-related macular degeneration eligible for ranibizumab. Expert Rev. Ophthalmol., 7:219–225, 2012.

32.

Inoue

, Arakawa

, Yamane

, and Kadonosono

Long-term results of intravitreal ranibizumab for the treatment of retinal angiomatous proliferation and utility of an advanced RPE analysis performed using spectral-domain optical coherence tomography. Br. J. Ophthalmol., 98:956–960, 2014.

33.

CATT Research Group, Martin

D.F.

, Maguire

M.G.

, Ying

G.S.

, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N. Engl. J. Med., 364:1897–1908, 2011.

34.

IVAN Study Investigators, Chakravarthy

, Harding

S.P.

, Rogers

C.A.

, Downes

S.M.

, et al. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology. 119:1399–1411, 2012.