Intravitreal Ranibizumab versus Thermal Laser

Euretina – Original Paper

Ophthalmologica

Ophthalmologica 2012;228:93–101 DOI: 10.1159/000337347

Received: December 12, 2011 Accepted after revision: February 2, 2012 Published online: May 9, 2012

Intravitreal Ranibizumab versus Thermal Laser Photocoagulation in the Treatment of Extrafoveal Classic Choroidal Neovascularization Secondary to Age-Related Macular Degeneration Ioannis D. Ladas a Irini P. Chatziralli a Athanasios I. Kotsolis a Maria Douvali b Ilias Georgalas a Panagiotis G. Theodossiadis b Alexandros A. Rouvas b a First Department of Ophthalmology, and b Second Department of Ophthalmology, University of Athens, Medical School of Athens, Athens, Greece

Key Words Age-related macular degeneration ⴢ Extrafoveal choroidal neovascularization ⴢ Ranibizumab ⴢ Thermal laser

Abstract Background: To compare the efficacy of thermal laser photocoagulation versus intravitreal ranibizumab for the treatment of extrafoveal classic choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). Methods: We conducted a retrospective study on 24 eyes with extrafoveal classic CNV secondary to AMD, treated either with thermal laser photocoagulation (group 1) or with intravitreal ranibizumab (group 2). Visual acuity, number of injections/sessions and recurrence rate were assessed. Results: The mean follow-up time was 23.6 8 2.26 and 19.1 8 9.74 months for group 1 and 2, respectively. Mean best corrected visual acuity (BCVA) of groups 1 and 2 was 0.59 8 0.32 and 0.46 8 0.30 logMAR, respectively (p = 0.343). At the end of the follow-up, mean BCVA of group 1 was 0.92 8 0.35 and of group 2 0.16 8 0.12 logMAR and differed statistically compared to baseline (p = 0.02 and p = 0.006, respectively). There was a statistically significant difference between the two groups as far as BCVA at the end of the follow-up was concerned (p ! 0.0001). The patients in group 1 received on

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average 1.38 sessions of thermal laser photocoagulation, while patients in group 2 received on average 4 injections of ranibizumab. The recurrence rate in the laser group was 84.6%, while in the ranibizumab group it was 18.2% (p ! 0.001). Specifically, the mean time of recurrence in the laser group was 11.5 months, whereas in the ranibizumab group it was 18 months (p = 0.048). Conclusion: Intravitreal ranibizumab showed promising results in BCVA improvement and decrease in macular thickness in patients with extrafoveal classic CNV due to AMD, with a small number of injections. Laser photocoagulation treatment presented worsening in BCVA and high recurrence rate in our study with long-term follow-up. Copyright © 2012 S. Karger AG, Basel

Introduction

Choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) is a leading cause of central vision loss [1, 2]. CNV can be divided morphologically into classic and occult forms, based on its appearance on fluorescein angiography (FA) [2]. Both of the two components can occur within the same lesion, creating four subgroups of CNV: classic with no occult Alexandros A. Rouvas, MD, PhD 2nd Department of Ophthalmology, ‘Attikon’ University Hospital 1, Rimini Street, Haidari GR–12462 Athens (Greece) Tel. +30 210 864 0087, E-Mail alexander.rouvas @ gmail.com

component, classic with occult component, minimally classic and occult with no classic component [2]. Specifically, classic CNV is characterized by an area of choroidal hyperfluorescence with well-demarcated boundaries than can be discerned in the early phase of the FA, while occult CNV is poorly defined with less precise features on the early frames and late-phase leakage of an undetermined source [1, 2]. As far as topographic classification is concerned, CNV can be classified as subfoveal (0 ␮m from the centre of the foveal avascular zone), juxtafoveal (1–199 ␮m from the centre of the foveal avascular zone) and extrafoveal (1200 ␮m from the centre of the foveal avascular zone) [2]. Several therapeutic alternatives, including thermal laser photocoagulation [3–12], photodynamic therapy (PDT) [13–16], surgical removal of CNV [17] or intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections [18–28], have been shown to be effective in the treatment of CNV due to AMD. Nevertheless, the majority of studies about CNV treatment concerned subfoveal or juxtafoveal CNV lesions. In fact, extrafoveal classic CNV with no occult component is a relatively rare entity [1], because AMD is a chronic situation and patients are old, therefore the occult component is present. Currently, CNV secondary to AMD is treated with anti-VEGF agents, independently of angiographic profile, although there is limited information on the intravitreal anti-VEGF treatment against extrafoveal classic CNV with no occult component. In addition, no comparative trial of laser photocoagulation with anti-VEGF agents against extrafoveal CNV associated with AMD has been performed [1]. However, in the era of anti-VEGF agents, it would not be feasible or ethical to conduct a prospective study comparing laser photocoagulation and anti-VEGF agents for the treatment of CNV due to AMD, given the fact that anti-VEGF has become the ‘gold standard’. In the light of the above, the purpose of our study was to compare retrospectively the efficacy of thermal laser photocoagulation versus intravitreal ranibizumab for the treatment of extrafoveal classic CNV with no occult component secondary to AMD in two groups with similar topographic and angiographic characteristics of CNV.

Materials and Methods We conducted a retrospective study on 24 eyes of 24 consecutive patients with extrafoveal classic CNV with no occult component secondary to AMD, treated either with thermal laser photocoagulation (group 1, n = 13) or with intravitreal ranibizumab (group 2, n = 11) in our department. Since 2007, we have used in-

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Ophthalmologica 2012;228:93–101

travitreal ranibizumab for the treatment of all CNV due to AMD, independently of angiographic profile. As a result, all medical charts were reviewed to find patients with similar topographic and angiographic characteristics of extrafoveal classic CNV with no occult component due to AMD, treated with thermal laser photocoagulation since 1998, when laser was the only therapeutic alternative for CNV, so as to compare the efficacy of the two treatment modalities. The two matched study groups were composed of those patients who met the eligibility criteria. Inclusion criteria consisted of age 150 years, eyes with documented exudative AMD and symptomatic CNV, fluorescein angiographic evidence of classic CNV lesions, with the foveal edge 200–2,000 ␮m from the geometric centre of the foveal avascular zone and minimum of 9-month follow-up period (once the diagnosis of CNV was made). Exclusion criteria were any of the following: occult CNV based on FA, subfoveal or juxtafoveal CNV, blood that covered the real boundaries of CNV, tearing of the retinal pigment epithelium, pigment epithelial detachment, previous thermal laser photocoagulation, previous anti-angiogenic treatment, previous PDT, proton beam irradiation, intraocular surgery ! 2 months before entry in the study, active intraocular inflammation or administration of topical and/or systemic corticosteroids in the previous 2 months. Moreover, patients with diabetes mellitus, high myopia (1 6 diopters, axial length 125 mm), cystoid macular edema or CNV secondary to inflammatory cause were excluded from the study. The study was in accordance with the tenets of the Declaration of Helsinki and was approved by the appropriate institutional review board. Written informed consent was obtained by all patients before entering the study. All patients underwent best-corrected visual acuity (BCVA) measurement using the Snellen charts, slit-lamp examination and indirect ophthalmoscopic fundus examination at baseline and follow-up visits. Each eye underwent FA using Topcon (Topcon, Medical Systems, Inc., Oakland, Calif., USA) from 1998 until 2004, HRA (Heidelberg Retina Angiograph; Heidelberg Engineering, Heidelberg, Germany) from 2004 until 2008 and Spectralis (Spectralis, Heidelberg Engineering, Heidelberg, Germany) after 2008. In group 1, FA was performed at baseline, months 1, 2 and 3, and then every 3 months thereafter and in group 2 at baseline and every 4 months. Furthermore, patients in ranibizumab group underwent optical coherence tomography (OCT) scans using the Stratus OCT (Carl Zeiss Meditec, Dublin, Calif., USA) for the measurement of macular thickness at baseline and every month thereafter. OCT scans and FAs were performed by the same experienced technician. Patients were examined promptly if they presented acute visual impairment. Retreatment, with the same therapeutic scheme in each group, was considered in case of recurrence. In group 1, recurrence was based on FA findings (leakage from new vessels at the site of previous lesions) and in group 2 it was defined as in the PrONTO study after CNV reactivation (new macular hemorrhages, new classic CNV, evidence of recurrence, fluid in OCT, increase of macular thickness in OCT with visual loss) [28]. The diagnosis of CNV was detected from fundus biomicroscopy (serous retinal detachment with or without retinal hemorrhages), FA (presence of early-phase hyperfluorescence with latephase leakage) and OCT in group 2 (hyperreflective area above the damaged retinal pigment epithelial level with intraretinal fluid/increased foveal thickness and/or serous foveal detachment).

Ladas /Chatziralli /Kotsolis /Douvali / Georgalas /Theodossiadis /Rouvas

Regarding the topographic and morphologic CNV characteristics, only patients with extrafoveal and predominantly classic CNV with no occult component were included in our study from 1998 to 2010. Thermal laser photocoagulation was performed according to a standard treatment protocol [3, 8]. The desired end point for the intensity of the laser lesion was the creation of a uniformly white lesion. We applied a ‘mapping’ technique, which has been described as a ‘guided’ laser treatment for other retinal diseases, such as diabetic retinopathy or diffuse retinal pigment epitheliopathy, in order to provide accuracy and safety in laser treatment [29, 30]. Additionally, with the ‘mapping’ technique we excluded the presence of persistent CNV, so as to review patients 1 month after laser treatment. Therefore, the real boundaries of CNV were overlaid from the early phases of FA on a pretreatment red-free photograph, with the aid of the digitized FA software system. After laser treatment, we performed again a red-free photograph and the boundaries of thermal laser burn were checked with the ‘mapping’ technique, so as to be the same with CNV boundaries that we had defined initially. If they were different, we applied laser photocoagulation once more. All lesion components were to be covered with laser treatment. Additionally, treatment was to extend 100 ␮m beyond the peripheral boundaries of all lesion components except blood. The protocol for treatment to the lesion boundary specified a 200- to 500-␮m spot with 0.2- to 0.5-second duration. Photocoagulation was applied first to a border 100 ␮m beyond the peripheral boundaries of all lesion components except thick blood. As far as blood was concerned, photocoagulation was applied to the border of the blood rather than 100 ␮m beyond it. Then the area within the boundaries of the lesion was treated with burns of the same spot size but with 0.5- to 1.0-second duration. In the ranibizumab group, the patients received 0.5 mg intravitreal ranibizumab (Lucentis쏐, Novartis) at baseline and on a monthly basis for the next 2 months (a total of three injections). In case of persistence or recurrence of subretinal fluid or intraretinal fluid according to OCT, and/or clinically detected new hemorrhages or new classic CNV according to FA, injections were administered to the patients on a monthly schedule, according to need. All the injections were performed under standard sterile conditions. Topical antibiotics were administered to all patients 4 times a day for 5 days after the injection. The visual acuity measurements were converted to logarithm of the minimum angle of resolution units (logMAR) for statistical reasons. All variables were tested for normal distribution with the Kolmogorov-Smirnov test. The t test for independent samples or Mann-Whitney-Wilcoxon test were used for comparisons of nominal variables between the two groups, as appropriate. A p value of !0.05 was considered significant. Statistical analysis was performed using SPSS 17.0 (SPSS, Inc., Chicago, Ill., USA).

Results

Group 1 included 13 patients (mean age 74.5 8 5.5 years) with a male:female ratio of 9:4, while 11 patients (mean age 74.9 8 5.8 years) with a male:female ratio of 6:5 participated in group 2. The data of the two groups Treatment Modalities for Extrafoveal Classic CNV due to AMD

Table 1. Data of patients treated with thermal laser photocoagula-

tion Case

1 2 3 4 5 6 7 8 9 10 11 12 13

Age Sex years

71 74 82 67 85 79 77 65 66 75 78 75 80

male male female male female female male male male male male male female

VA, logMAR baseline

end

0.5 0.5 1 0.5 0.7 0.15 1 0.1 0.4 1 1 0.4 0.4

1 0.7 1.6 0.5 1 1 1.3 0.5 1 1 1 1 0.3

Laser Follow-up Recursessions months rence n

1 1 1 1 1 1 1 1 3 1 3 1 2

23 28 21 23 26 24 24 25 21 26 21 24 21

1 1 1 – 1 1 1 1 3 – 3 1 2

VA = Visual acuity.

are summarized in tables 1 and 2. All patients completed at least 9 months of follow-up after their initial evaluation. The mean follow-up time for group 1 was 23.6 8 2.26 months (range: 21–28) and for group 2 19.1 8 9.74 months (range: 9–36). The mean (8SD) BCVA of groups 1 and 2 was 0.59 8 0.32 logMAR (mean; range: 0.1–1) and 0.46 8 0.30 logMAR (range: 0.1–1), respectively (p = 0.343). At the end of the follow-up, the mean BCVA of group 1 was 0.92 8 0.35 logMAR (range: 0.3–1.6) and differed statistically compared to baseline (p = 0.02; fig. 1). Specifically, there was a decrease in BCVA in 9 patients (69.2%), 3 patients (23.1%) presented stability in BCVA and only 1 patient (7.7%) had an improvement at the end of the follow-up. In the ranibizumab group, the mean BCVA at the end of the follow-up was 0.16 8 0.12 logMAR (range: 0–1) and differed statistically in comparison with baseline (p = 0.006; fig. 1). Nevertheless, all patients presented a considerable improvement in BCVA (fig. 2). There was a statistically significant difference between the two groups as far as BCVA at the end of the follow-up is concerned (p ! 0.0001). The mean macular thickness in ranibizumab group was 254 8 16 ␮m (range: 235–285) at baseline and 219 8 8 ␮m (range: 201–230) at the end of the follow-up. There was a statistically significant difference between baseline and the end point of the follow-up (p ! 0.001). Ophthalmologica 2012;228:93–101

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Table 2. Data of patients treated with intravitreal ranibizumab

Case

1 2 3 4 5 6 7 8 9 10 11

Age years

Sex

70 76 79 78 71 66 72 81 83 75 68

male male female female female male male female female male male

CFT, ␮m

VA, logMAR baseline

end

baseline

end

Injections n

Follow-up months

Recurrence

0.1 0.5 1.0 1.0 0.5 0.15 0.4 0.5 0.4 0.4 0.15

0 0.2 0.2 0.4 0.2 0.1 0.1 0.1 0.2 0.3 0

245 268 250 265 289 238 260 253 241 250 235

230 221 218 220 228 215 225 222 218 201 211

3 3 5 4 3 2 3 5 3 6 7

36 12 15 12 9 13 12 17 21 27 36

– – – – – – – – – 1 2

Error bars: ±2 SE Baseline End

0.80

0.60

0.40

Laser photocoagulation Lucentis

100

80 Patients (%)

Mean BCVA (logMAR units)

1.00

120

Color version available online

1.20

Color version available online

VA = Visual acuity; CFT = central foveal thickness.

60

40

0.20

20

0 Laser photocoagulation Group

Lucentis

0 Worse

Same

Better

Fig. 1. Mean visual acuity in the two groups at baseline and at the

Fig. 2. Comparison of the changes in visual acuity between the

end of the follow-up.

two groups at the end of the follow-up.

The patients in group 1 received on average 1.38 sessions of thermal laser photocoagulation, while patients in group 2 received on average 4 injections of ranibizumab. The recurrence rate in the ranibizumab group (fig. 3, 4) was 18.2%, whereas in the laser group it was 84.6%, which differed statistically compared to group 2 (p ! 0.001). Specifically, the mean time of recurrence in the laser group was 11.5 8 13.7 months, whereas in the ranibi-

zumab group it was 18 8 5.3 months (p = 0.048). In addition, 8 patients (61.5%) in the laser group developed subfoveal CNV and were treated with PDT (fig. 5), while 3 patients (23.1%) received again a therapeutic scheme with laser photocoagulation (fig. 6, 7). The 2 patients with recurrent CNV in group 2 were treated with intravitreal ranibizumab.

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A

B

C

D

E

F

G

H

Fig. 3. Case 9 from group 2 (Lucentis). A–C Early phase of FA at baseline, showing

the classic CNV with no occult component and late phase of FA with simultaneous OCT scan at baseline, showing leakage of the dye in late frames, subretinal fluid and diffuse macular edema in OCT. D–F FA (early phase), FA (late phase) and simultaneous OCT, respectively, 3 months after baseline, with 3 intravitreal injections of ranibizumab. There is no active CNV and no subretinal fluid in OCT. G–I FA (early phase), FA (late phase) and simultaneous OCT, respectively, 18 months after baseline. There is no active component of CNV which would necessitate a re-injection.

A

B

D

E

I

C

Fig. 4. Case 8 from group 2 (Lucentis). A–C FA (early phase), FA (late phase) and

simultaneous OCT, respectively, at baseline, showing classic CNV with no occult component with presence of leakage of the dye in the late phase of FA and a small amount of intraretinal fluid and diffuse macular edema in the respective area in OCT. D–F FA (early phase), FA (late phase) and simultaneous OCT, respectively, 12 months after baseline, with 5 intravitreal injections of ranibizumab. There is no presence of active CNV and no subretinal fluid in OCT.

Treatment Modalities for Extrafoveal Classic CNV due to AMD


F

97

A

E

F

H

I

Fig. 5. Case 1 from group 1 (thermal laser). A–D Red-free image,

early- and late-phase FA, respectively, at baseline showing classic CNV with no occult component, and ‘mapping technique’ image, where the large circle represents the borders of CNV and the small circle the foveal avascular zone, which we should avoid when performing thermal laser. E–G Red-free image and early-phase FA, respectively, 1 month after baseline and thermal laser showing no

Discussion

The principal message of our study is that intravitreal ranibizumab provided promising results in terms of visual acuity improvement and macular thickness decrease in patients with extrafoveal classic CNV with no occult component secondary to AMD, exhibiting a low recurrence rate (18.2%) with a small number of intravitreal injections. In contrast, thermal laser photocoagulation had 98

D

C

B


G

J

persistent or new CNV and red-free image 18 months after baseline, showing new hemorrhage at the fovea. H–J Early-phase FA 18 months after baseline with subfoveal CNV, red-free image and early-phase FA, respectively, 23 months after baseline after treatment with PDT sessions, showing enlargement of subfoveal CNV, causing eventually severe deterioration in visual acuity.

84.6% recurrence rate and presented deterioration in visual acuity. The Macular Photocoagulation Study was the largest prospective clinical trial introducing laser treatment of CNV [3, 5–12] in AMD and suggesting that lesion morphology played an important role in the prognosis and treatment of CNV [10, 12]. Although the first results of the Macular Photocoagulation Study were promising, the long-term follow-up showed that almost half of the paLadas /Chatziralli /Kotsolis /Douvali / Georgalas /Theodossiadis /Rouvas

A

Fig. 6. Case 9 from group 1 (thermal laser). A–C Early- and late-phase FA, respectively,

at baseline, showing active classic CNV with no occult component and ‘mapping technique’ image, where the large circle represents the borders of CNV and the small circle the foveal avascular zone, which we should avoid when performing laser. D, E FA 3 months after baseline, showing extrafoveal recurrence of CNV and final FA 21 months after baseline, with 3 laser sessions. The patient exhibited a decrease in visual acuity from 0.4 logMAR at baseline to 1 logMAR at the end of the follow-up.

A

D

B

B

C

E

C

Fig. 7. Case 11 from group 1 (thermal laser). A–C FA at baseline, showing classic CNV with no occult component nasal to the fovea; FA 12 months after laser treatment. There is no recurrence of CNV, but there is a new classic CNV temporal to the fovea. Final FA 21 months after initial laser, after 3 sessions of thermal laser, where there is again an extrafoveal recurrence of CNV at the site of previous laser treatment at 12 months.

tients experienced recurrence with development of subfoveal CNV [7, 9, 11]. Other studies have also shown the beneficial effect of laser photocoagulation in selected cases of exudative AMD; however, major limitations were the high recurrence rate, the enlargement of the laser treatment scar causing some degree of scotoma, and the difficulty in the delineation of the CNV [1, 4]. Therefore,

laser photocoagulation remained a significant treatment alternative mostly for extrafoveal well-defined CNV (classic) secondary to AMD [7]. In our study, there was a statistically significant decrease in visual acuity in the laser group. In addition, 84.6% of patients developed recurrence of CNV in the long-term follow-up, in accordance with previous studies.



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Nowadays, anti-VEGF agents are the most popular treatment for CNV. According to the ANCHOR and MARINA studies, patients presented an improvement of 11.3 and 7.2 letters, respectively, in mean visual acuity after intravitreal ranibizumab injections [19, 20, 25–27]. Nevertheless, they needed 24 injections in the 24-month follow-up, while patients in PrONTO study needed an average of 9.9 injections for the same period of follow-up, presenting similar improvement in visual acuity (11.1 letters) [28]. In our study, there was also an improvement in mean BCVA in the ranibizumab group from 0.44 logMAR at baseline to 0.24 logMAR at the end of the follow-up, as well as a decrease in mean macular thickness, with an average number of 4 injections for 19.1 8 9.7 months of follow-up. It is worth mentioning that the PrONTO study introduced an OCT-guided variable dosing regimen, starting with 3 initial monthly injections and continuing according to need, based on the evolution of visual acuity and OCT findings [28]. We followed the PrONTO study for scheduling the intravitreal injections, and noticeably there was a considerable improvement in BCVA with a relatively small number of injections. The efficacy of ranibizumab for the treatment of nonsubfoveal CNV due to AMD mainly in terms of preventing subfoveal progression was also shown by Arias et al. [31], although the authors had included not only classic but also occult and minimally classic CNV. In addition, Han et al. [32] in their retrospective study suggested that anti-VEGF therapy, combined or not with PDT, could be used as an alternative to the ‘gold standard’ laser photocoagulation for non-subfoveal CNV. In our study, comparing the two regimens, i.e. thermal laser photocoagulation and intravitreal ranibizumab for extrafoveal classic CNV due to AMD, there is a superiority of intra-

vitreal ranibizumab in terms of visual acuity improvement. Furthermore, the recurrence rate was very low in the ranibizumab group in contrast to the laser group, which presented 84.6% recurrence, although we used the ‘mapping’ technique to be more accurate in thermal laser appliance. Obvious limitations of this study were the small number of patients in each group and the retrospective design of the study, which led to different follow-up time between the two groups and possible selection bias. However, as previously cited, extrafoveal classic CNV with no occult component secondary to AMD represents a rare clinical entity [1, 33] and the design of a prospective study comparing several treatment modalities for this form remains a challenge. Another limitation of our study, which needs to be declared, is that OCT has not been performed in group 1, but when laser photocoagulation treatment was performed, there was no OCT technology. In conclusion, our study suggests that intravitreal injections of ranibizumab have shown promising results in BCVA improvement and decrease in macular thickness in patients with extrafoveal classic CNV with no occult component associated with AMD. Laser photocoagulation treatment resulted in worsening in BCVA and a high recurrence rate in our study with long-term follow-up. Further studies are needed to confirm the exact benefit and standardize the optimal treatment regimen.

Disclosure Statement None of the authors has a conflict of interest with the submission. No financial support was received for this submission.

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