Intravitreal Bevacizumab for Subfoveal Choroidal Neovascularization in Age-Related Macular Degeneration at Twenty-four Months: The Pan-American Collaborative Retina Study

doi:10.1016/j.ophtha.2010.01.056

Ophthalmology

Volume 117, Issue 10, October 2010, Pages 1974-1981.e1

Presented in part at: the Joint Meeting of the American Academy of Ophthalmology and the Pan-American Association of Ophthalmology, October 2009, San Francisco, California.

https://doi.org/10.1016/j.ophtha.2010.01.056 Get rights and content

Purpose

To report the 24-month anatomic and Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) response after primary intravitreal bevacizumab (IVB) (Avastin; Genentech Inc., San Francisco, CA) (1.25 or 2.5 mg) in patients with subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD).

Design

Retrospective, multicenter, interventional, comparative case series.

Participants

We reviewed the clinical records of 180 consecutive patients (207 eyes) with subfoveal CNV secondary to AMD at 9 centers from 8 countries.

Methods

Patients were treated with at least 1 injection of IVB 1.25 mg (124 eyes [59.9%]) or 2.5 mg (83 eyes [40.1%]). Patients underwent ETDRS BCVA testing, ophthalmoscopic examination, optical coherence tomography (OCT), and fluorescein angiography (FA) at baseline and 1-, 3-, 6-, 12-, and 24-month visits.

Main Outcome Measures

Changes in BCVA and OCT.

Results

The mean age of our patients was 74.3±7.5 years. The mean number of IVB injections per eye was 5.1 (range, 1–24 injections). In the 1.25 mg group, baseline BCVA improved from 20/235 (logarithm of the minimum angle of resolution [logMAR] 1.07) to 20/172 (logMAR 0.92) at 24 months (P<0.0001). Similar BCVA changes were observed in the 2.5 mg group. At baseline, the mean central macular thickness (CMT) by OCT in the 1.25 mg group was 308.4±127.52 μm, which was reduced to 269.35±97.92 μm, 262.1±94.81 μm, 264.03±97.06 μm, 245.91±89.52 μm, and 249.27±89.14 μm at 1, 3, 6, 12, and 24 months, respectively (P<0.0001). Similar changes were observed in the 2.5 mg group. In the 2.5 mg group, systemic complications included 2 new cases (2.6%) of arterial hypertension, 1 case (1.3%) of stroke, and 1 case (1.3%) of death.

Conclusions

Primary IVB at a dose of 1.25 or 2.5 mg seems to provide stability or improvement in BCVA, OCT, and FA in subfoveal CNV secondary to AMD at 24 months. Our results show no significant difference regarding BCVA with IVB at doses of 1.25 or 2.5 mg.

Financial Disclosure(s)

The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Section snippets

Patients and Methods

We reviewed the clinical records of consecutive patients with CNV secondary to AMD who were treated with off-label IVB between September 2005 and July 2007 at 9 institutions in Venezuela, Brazil, Puerto Rico, Peru, Colombia, Costa Rica, Spain, and Argentina. A total of 207 eyes of 180 consecutive patients with subfoveal CNV secondary to AMD, a mean age of 74.3±8 years, and 24 months of follow-up were identified and included for this analysis. Institutional review board/ethics committee approval

Results

A total of 128 patients (71.1%) were Hispanic, and 52 patients (28.9%) were Caucasian. Patients had a mean age of 74.3±8 years (range, 54–93 years), and 66.1% were female (61 men and 119 women). All eyes were followed for 24 months. A summary of the demographics and baseline characteristics of our patients is shown in Table 1.

Within 1 month after the initial bevacizumab injection, improvements in BCVA and CMT measurements were observed, and these significant changes continued throughout the

Discussion

The majority of eyes that were treated with primary IVB at doses of 1.25 or 2.5 mg showed anatomic and functional improvement at 24 months. Both leakage and macular thickening caused by CNV were significantly reduced. At 1 month, the mean CMT measurements decreased from 349.6±131.32 μm to 272.24±87.48 μm (P<0.001), and this overall improvement continued throughout the 24-month follow-up. In addition, 43.5% of consecutive eyes gained ≥2 lines of ETDRS at the 24-month time point. However, 13.5%

References (35)

R. Klein et al.
The epidemiology of age-related macular degeneration
Am J Ophthalmol
(2004)
F.G. Holz et al.
Pathogenesis of lesions in late age-related macular disease
Am J Ophthalmol
(2004)
Z.F. Bashshur et al.
Intravitreal bevacizumab for the management of choroidal neovascularization in age-related macular degeneration
Am J Ophthalmol
(2006)
U.H. Spandau et al.
Retinal pigment epithelium tear after intravitreal bevacizumab for exudative age-related macular degeneration
Am J Ophthalmol
(2006)
D.J. D'Amico
Diseases of the retina
N Engl J Med
(1994)
Potential public health impact of Age-Related Eye Disease Study results: AREDS report no. 11
Arch Ophthalmol
(2003)
Causes and prevalence of visual impairment among adults in the United States
Arch Ophthalmol
(2004)
Prevalence of age-related macular degeneration in the United States
Arch Ophthalmol
(2004)
F.L. Ferris et al.
Age-related macular degeneration and blindness due to neovascular maculopathy
Arch Ophthalmol
(1984)
N. Ferrara
Vascular endothelial growth factor: basic science and clinical progress
Endocr Rev
(2004)

J.W. Miller et al.

Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model

Am J Pathol

(1994)

A.P. Adamis et al.

Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate

Arch Ophthalmol

(1996)

R. Amin et al.

Growth factor localization in choroidal neovascular membranes of age-related macular degeneration

Invest Ophthalmol Vis Sci

(1994)

M. Kliffen et al.

Increased expression of angiogenic growth factors in age-related maculopathy

Br J Ophthalmol

(1997)

M.G. Krzystolik et al.

Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment

Arch Ophthalmol

(2002)

E.S. Gragoudas et al.

Pegaptanib for neovascular age-related macular degeneration

N Engl J Med

(2004)

Enhanced efficacy associated with early treatment of neovascular age-related macular degeneration with pegaptanib sodium: an exploratory analysis

Retina

(2005)

Cited by (35)

Evolution of Intravitreal Therapy for Retinal Diseases—From CMV to CNV: The LXXIV Edward Jackson Memorial Lecture
2018, American Journal of Ophthalmology
Citation Excerpt :
Ophthalmologists had proceeded cautiously, treating only when there was evidence of disease activity. PRN dosing appeared to produce good visual acuity results, and monthly injections had not been required for many patients.74–76 A small study of PRN dosing with ranibizumab was performed and yielded encouraging results.77
To present the evolution of intravitreal therapy for retinal diseases and its impact on clinical practice.
Retrospective literature review and personal perspective.
Retrospective literature review and personal perspective.
Pharmacotherapeutic advances in retinal disease have been remarkable over the last 25 years. Almost all of the new drugs developed have required intravitreal administration to be highly effective, leading to an exponential increase in the annual number of intravitreal injections given. The use of intravitreal antibiotic injections to treat endophthalmitis, usually on a one-time basis, first familiarized ophthalmologists with this method of drug delivery. Ganciclovir was the first widely available, relatively inexpensive compounded drug that was used for repeat intravitreal injection to treat a chronic retinal disease, followed by triamcinolone for diabetic macular edema and bevacizumab for neovascular age-related macular degeneration. Ganciclovir was formulated for sustained-release drug delivery to avoid frequent intravitreal injections, a goal that has been more elusive for anti-VEGF drugs. Political obstacles encountered while conducting some of the trials to evaluate these treatments were substantial. Addressing the issues they raised led to important national policy changes that will impact the conduct of future clinical trials. The first comparative efficacy trial of intravitreal therapies was the Comparison of AMD Treatments Trials (CATT). The primary results from CATT and the many publications that followed continue to shape the use of intravitreal therapy today.
Intravitreal therapy has proven highly effective for the treatment of many retinal diseases. The treatment burden for patients from numerous injections, the cost to health care systems, and the impact on workflows in clinical practice have been substantial. Efforts to develop effective intravitreal therapies with reduced treatment burden and cost are ongoing.
Prognostic factors of eyes with naïve subfoveal myopic choroidal neovascularization after intravitreal bevacizumab
2013, American Journal of Ophthalmology
To determine the efficacy of 1 intravitreal bevacizumab injection followed by pro re nata (1 + PRN) injection in cases of subfoveal myopic choroidal neovascularization (CNV) and to identify CNV-recurrence–related prognostic factors.
Retrospective observational case series.
In total, 103 eyes of 89 consecutive naive patients who had subfoveal myopic CNV and had been followed-up for at least 2 years were included. Of those eyes, 24 had recurrences. The remaining eyes were stable after the initial treatment.
The average patient age was 51.1 ± 15.2 years. The average follow-up duration was 44.1 ± 12.7 months. At baseline and at the 1-year, 2-year, and final visits, the average best corrected visual acuities (BCVAs) were 0.57 ± 0.45, 0.38 ± 0.51, 0.40 ± 0.52, and 0.41 ± 0.41 logMAR, respectively. The recurrence rate during follow-up was 23.3%. The BCVA improved by 0.2 logMAR after 2.7 injections in the eyes without recurrence but by only 0.08 logMAR after 6.9 injections in the eyes with recurrence. In univariate analysis, recurrence was associated with older age, more myopic refraction, thinner choroid, larger CNV lesions, and subfoveal hemorrhage at baseline. In multivariate analysis, only baseline CNV lesion size associated significantly with CNV recurrence (P = 0.002). Recurrence, baseline BCVA, choroidal thickness, and CNV size associated significantly with final BCVA (P = 0.026, <0.0001, 0.007, and 0.002, respectively). Baseline choroidal thickness, CNV size, age, and presence of lacquer cracks associated significantly with injection number (P < 0.0001, <0.0001, 0.026, and 0.035, respectively).
1 + PRN intravitreal bevacizumab monotherapy effectively stabilized subfoveal myopic CNV. The CNV size, the baseline BCVA, and the choroidal thickness were the main prognostic factors of subfoveal myopic CNV after 1 + PRN injection of bevacizumab.
Bevacizumab versus ranibizumab in the treatment of exudative age-related macular degeneration: A retrospective study of 58 patients
2012, Journal Francais d'Ophtalmologie
Citation Excerpt :
In 2006, Spaide et al. (266 eyes) found a statistically improvement of the mean BCVA from 20/184 to 20/109 at the 3-month follow-up [16]. In 2010, Arevalo et al. (207 eyes) retrospectively investigated the efficacy of bevacizumab in the treatment of wet AMD during 24 months of follow-up [17]. They show a significant improvement of BCVA at 24 months.
To compare the efficacy and safety of bevacizumab versus ranibizumab in the treatment of patients with neovascular age-related macular degeneration (AMD).
Retrospective case-controlled series of 30 patients treated with intravitreal bevacizumab and 28 patients treated with intravitreal ranibizumab for exudative AMD. Main outcomes measured included best-corrected visual acuity (BCVA), central macular thickness (CMT) and foveal thickness, quantity of subretinal fluid, neovessel size and total number of injections over the first year treatment period. A secondary outcome was the report of any adverse events in both groups.
BCVA stabilized and increased from LogMAR 0.70 to 0.47 in the bevacizumab group and from 0.55 to 0.54 in the ranibizumab group (P > 0.05). CMT decreased in the bevacizumab group from 369 to 284 μm and in the ranibizumab group from 340 to 271 μm (P > 0.05). The number of injection was significantly lower (4.8) in the bevacizumab group than in the ranibizumab group (5.8) (P < 0.05). No serious ocular adverse events were noted in both groups.
This retrospective study failed to show a difference in visual and anatomic outcomes between bevacizumab and ranibizumab. The number of re-treatment was lower in the bevacizumab group (P = 0.03).
Évaluer l’efficacité et la tolérance du bevacizumab versus ranibizumab dans la prise en charge des patients atteints de la forme néovasculaire de la dégénérescence maculaire liée à l’âge (DMLA).
Il s’agit d’une série rétrospective témoignée chez 30 patients traités par injection intravitréenne du bevacizumab et 28 patients traités par injection intravitréenne du ranibizumab pour la DMLA exsudative. Les résultats principaux enregistrés comprennent l’acuité visuelle (AV), l’épaisseur maculaire central (EMC) et l’épaisseur fovéolaire, la quantité du fluide sous-rétinien, les dimensions des nouveaux vaisseaux et le nombre d’injections pendant la première année du traitement. Un résultat secondaire était l’enregistrement d’événement défavorable dans chaque groupe.
L’AV s’est stabilisée et améliorée de 0,70 à 0,47 LogMAR dans le groupe bevacizumab, et de 0,55 à 0,54 dans le groupe ranibizumab (p < 0,05). L’EMC a diminué dans le groupe bevacizumab de 369 μm à 284 μm, et dans le groupe ranibizumab de 340 μm à 271 μm (p < 0,05). Le nombre d’injections a été significativement inférieur (4,8) chez le groupe bevacizumab par rapport au groupe ranibizumab (5,8) (p < 0,05). Aucun événement défavorable oculaire sérieux n’a été enregistré dans les deux groupes.
Cette étude rétrospective n’a pas montré de différence de résultats fonctionnels ou anatomiques entre les deux groupes.
Bevacizumab for neovascular age-related macular degeneration using a treat-and-extend regimen: Clinical and economic impact
2012, American Journal of Ophthalmology
Citation Excerpt :
This was reportedly because the monthly follow-up originally intended in this group was not possible, highlighting the difficulty associated with frequent office visits in clinical practice.18 Several studies have evaluated the safety and efficacy of intravitreal bevacizumab in the treatment of neovascular AMD using individualized dosing regimens.3–10 These reports have served as a basis for using intravitreal bevacizumab in clinical practice to treat neovascular AMD.
To evaluate the visual outcomes, number of injections, and direct medical cost of a treat-and-extend regimen in managing neovascular age-related macular degeneration with intravitreal bevacizumab.
Retrospective, interventional, consecutive case series.
Seventy-four eyes of 73 patients with treatment-naïve neovascular age-related macular degeneration from a single clinical practice were treated monthly with intravitreal bevacizumab until no intraretinal or subretinal fluid was observed on optical coherence tomography. The treatment intervals then were lengthened sequentially by 2 weeks until signs of exudation recurred and then were reduced accordingly to maintain an exudation-free macula. Main outcomes measured included mean change from baseline visual acuity, proportion of eyes losing fewer than 3 and gaining 3 or more Snellen visual acuity lines at 1 year of follow-up, annual mean number of injections, optical coherence tomography mean central retinal thickness change from baseline, mean maximum period of extension, adverse events, and mean direct annual medical cost.
The mean follow-up period was 1.41 years. Mean Snellen visual acuity improved from 20/230 at baseline to 20/109 at 12 months (P < .001) and 20/106 at 24 months (P < .001). The mean number of injections over the first year was 7.94. The mean optical coherence tomography central retinal thickness decreased from 316 to 239 μm at 12 months (P < .001). The mean direct medical cost over the first year was $3493.85.
Eyes with neovascular age-related macular degeneration experienced significant visual improvements on average when managed with intravitreal bevacizumab using a treat-and-extend regimen with fewer patient visits and injections along with lower costs compared with a fixed, monthly dosing regimen.
Real-world outcomes of intravitreal anti-vascular endothelial growth factor monotherapy in proliferative type 2 macular telangiectasia
2021, Graefe's Archive for Clinical and Experimental Ophthalmology
TANDEM TRIAL: A factorial randomised controlled trial of dose and review schedule of bevacizumab (A vastin) for neovascular macular degeneration in the e ast M idlands
2020, BMJ Open Ophthalmology

View all citing articles on Scopus

: Manuscript no. 2009-1328.

: This article contains online-only material. The following should appear online-only: Appendix 1.

: Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

: Supported in part by the Arevalo-Coutinho Foundation for Research in Ophthalmology, Caracas, Venezuela.

^⁎: For a complete listing of participating members of the Pan-American Collaborative Retina Study Group, see Appendix 1 (available at http://aaojournal.org).

View full text

Original articleIntravitreal Bevacizumab for Subfoveal Choroidal Neovascularization in Age-Related Macular Degeneration at Twenty-four Months: The Pan-American Collaborative Retina Study

Purpose

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Financial Disclosure(s)

Section snippets

Patients and Methods

Results

Discussion

Am J Ophthalmol

Am J Ophthalmol

Am J Ophthalmol

Am J Ophthalmol

Diseases of the retina

N Engl J Med

Potential public health impact of Age-Related Eye Disease Study results: AREDS report no. 11

Arch Ophthalmol

Causes and prevalence of visual impairment among adults in the United States

Arch Ophthalmol

Prevalence of age-related macular degeneration in the United States

Arch Ophthalmol

Age-related macular degeneration and blindness due to neovascular maculopathy

Arch Ophthalmol

Vascular endothelial growth factor: basic science and clinical progress

Endocr Rev

Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model

Am J Pathol

Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate

Arch Ophthalmol

Growth factor localization in choroidal neovascular membranes of age-related macular degeneration

Invest Ophthalmol Vis Sci

Increased expression of angiogenic growth factors in age-related maculopathy

Br J Ophthalmol

Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment

Arch Ophthalmol

Pegaptanib for neovascular age-related macular degeneration

N Engl J Med

Enhanced efficacy associated with early treatment of neovascular age-related macular degeneration with pegaptanib sodium: an exploratory analysis

Retina

Original article
Intravitreal Bevacizumab for Subfoveal Choroidal Neovascularization in Age-Related Macular Degeneration at Twenty-four Months: The Pan-American Collaborative Retina Study