Intravitreal Bevacizumab (Avastin) in the Treatment of Proliferative Diabetic Retinopathy

doi:10.1016/j.ophtha.2006.05.064

Ophthalmology

Volume 113, Issue 10, October 2006, Pages 1695-1705.e6

Presented in part at: American Academy of Ophthalmology Subspecialty Meeting, October 2005, Chicago, Illinois, and Royal Hawaiian Eye Meeting, January 2006, Wailea, Hawaii.

https://doi.org/10.1016/j.ophtha.2006.05.064 Get rights and content

Purpose

To report the biologic effect of intravitreal bevacizumab in patients with retinal and iris neovascularization secondary to diabetes mellitus.

Design

Interventional, consecutive, retrospective, case series.

Participants

Forty-five eyes of 32 patients with retinal and/or iris neovascularization secondary to diabetes mellitus.

Methods

Patients received intravitreal bevacizumab (6.2 μg–1.25 mg). Ophthalmic evaluations included nonstandardized Snellen visual acuity (VA), complete ophthalmic examination, fluorescein angiography, and optical coherence tomography.

Main Outcome Measures

Change in fluorescein angiographic leakage of the proliferative diabetic retinopathy (PDR). Secondary outcomes included changes in Snellen VA.

Results

No significant ocular or systemic adverse events were observed. All patients with neovascularization demonstrated by fluorescein angiography (44/44 eyes) had complete (or at least partial) reduction in leakage of the neovascularization within 1 week after the injection. Complete resolution of angiographic leakage of neovascularization of the disc was noted in 19 of 26 (73%) eyes, and leakage of iris neovascularization completely resolved in 9 of 11 (82%) eyes. The leakage was noted to diminish as early as 24 hours after injection. In addition to the reduction in angiographic leakage, the neovascularization clinically appeared to involute in many patients with a reduction in the caliber or presence of perfused blood vessels. In 2 cases, a subtle decrease in leakage of retinal or iris neovascularization in the fellow uninjected eye was noted, raising the possibility that therapeutic systemic levels were achieved after intravitreal injection. Recurrence of fluorescein leakage varied. Recurrent leakage was seen as early as 2 weeks in one case, whereas in other cases, no recurrent leakage was noted at last follow-up of 11 weeks.

Conclusions

Short-term results suggest that intravitreal bevacizumab is well tolerated and associated with a rapid regression of retinal and iris neovascularization secondary to PDR. A consistent biologic effect was noted, even with the lowest dose (6.2 μg) tested, supporting proof of concept. The observation of a possible therapeutic effect in the fellow eye raises concern that systemic side effects are possible in patients undergoing treatment with intravitreal bevacizumab (1.25 mg), and lower doses may achieve a therapeutic result with less risk of systemic side effects. Further study is indicated.

Section snippets

Patients and Methods

Initially, only patients with active iris neovascularization who were unresponsive to traditional treatment were considered for bevacizumab treatment. After a patient with iris and retinal neovascularization was treated and the retinal neovascularization was observed to involute (case 3; Fig 1 [available at http://aaojournal.org]), patients with retinal neovascularization alone were treated. Patients were not offered treatment if they had uncontrolled hypertension or a recent myocardial

Results

Of the 32 patients, 16 were female and 16 were male (Table 1 [available at http://aaojournal.org]). The mean age was 58 years. Follow-up ranged from 1 to 14 weeks, with mean and median follow-up of 5 weeks. The majority (39/45 [87%]) of eyes had received prior panretinal photocoagulation for active retinal or iris neovascularization associated with diabetic retinopathy. The injection appeared to be well tolerated in all patients. No patient developed uveitis, endophthalmitis, ocular toxicity,

Discussion

Since the Diabetic Retinopathy Study, panretinal photocoagulation has been the treatment of choice for PDR.¹⁸ It has proven to be remarkably effective and has saved vision in countless patients over the past several decades. However, it is a destructive therapy, with adverse side effects such as loss of peripheral visual field and night vision as well as exacerbation of macular edema and subsequent reduction of central vision.19, 20 In patients with a media opacity such as vitreous hemorrhage

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Comparison of photodynamic therapy with two different parameters combined with subconjunctival injection of bevacizumab for corneal neovascularization
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To the best of our knowledge, no studies have been performed to determine the optimal parameters of photodynamic therapy (PDT) combined with subconjunctival injection of bevacizumab for corneal neovascularization. This study aimed to compare the effect of photodynamic therapy with two different sets of parameters combined with subconjunctival injection of bevacizumab for corneal neovascularization.
Patients with stable corneal neovascularization (CNV) unresponsive to conventional treatment (topical steroid) were included in this study. Patients were divided into two groups, receiving PDT with two different sets of parameters (group 1 receiving fluence of 50 J/cm² at 15 min after intravenous injection of verteporfin with, group 2 receiving fluence of 150 J/cm² at 60 min after intravenous injection of verteporfin with). Subconjunctival injection of bevacizumab was performed immediately after PDT. All patients were followed for 6 months. Best-corrected visual acuity and intraocular pressure were evaluated, and slit-lamp biomicroscopy as well as digital photography were performed. Average diameter and cumulative length of corneal neovascular were measured to evaluate the corneal neovascularization.
Seventeen patients (20 eyes) were included in this study. At the last visit, the vision was improved in 12 eyes (60 %), steady in 4 eyes (20 %) and worsen in 4 eyes (20 %). The intraocular pressure (IOP) of all patients remained in normal range. A significant decrease in corneal neovascularization was showed in all the eyes after treatment. At 6 months after the combined treatment, the average diameter and cumulative length of vessels significantly decreased to 0.041 ± 0.023 mm (P < 0.05) and 18.78 ± 17.73 mm (P < 0.05), respectively, compared with the pretreatment data (0.062 ± 0.015 mm, 31.48 ± 18.21 mm). The reduction was more remarkable in group 2 compared to group 1.In group 1, the average diameter was 0.062 ± 0.013mm before and 0.056 ± 0.017mm after, the cumulative length of vessels was 38.66 ± 22.55mm before and 31.21 ± 17.30 after. In group 2, the date were 0.061 ± 0.016mm before and 0.029 ± 0.020mm after, 25.60 ± 8.95 mm before and 8.61 ± 8.26 mm. The reported complications included epithelial defect in four eyes, small white filaments in two eyes and corneal epithelial erosion in two eyes.
The PDT combined with subconjunctival injection of bevacizumab was effective for the chronic corneal neovascularization. A more promising treatment outcome was observed when PDT was performed at 60 min after intravenous injection of verteporfin with fluence of 150 J/cm². No serious complications or systemic events were observed throughout the follow-up period.
Medico-surgical management of intravitreal hemorrhage in diabetic patients
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L’hémorragie intravitréenne (HIV) est la principale complication de la rétinopathie diabétique proliférante et reste la première indication de la vitrectomie chez le patient diabétique. L’objectif de notre étude est de comparer notre gestion médicochirurgicale de l’HIV par rapport aux données de la littérature et rapporter les résultats fonctionnels de notre série. Nous avons étudié une série consécutive de 284 cas colligés sur une période de 2 ans dans deux structures tertiaires. Dans notre série, 90,1 % des patients avaient un diabète de type 2 et 70 % avaient une HBA1C supérieure à 7,5 %. Au fond de l’œil, 35,2 % des patients ont présenté une HIV stade 1, 42,6 % une HIV stade 2, 3,6 % une HIV stade 3, 5,2 % une HIV stade 4, tandis que 13,4 % de nos patients ont présenté une HIV associée à un décollement de rétine tractionnel. Dans notre étude, l’échographie oculaire, réalisée en cas d’inaccessibilité du fond d’œil, a permis d’objectiver un décollement de rétine échographique chez 8,8 % des cas. Le traitement médical a été suffisant chez 77,8 % des patients, tandis que 22,2 % de nos patients ont bénéficié d’une vitrectomie avec endophotocoagulation au laser argon et une injection d’anti-VEGF postopératoire. Le pelage des membranes fibrovasculaires tractionnelles et/ou des membranes épirétiniennes associées a été effectué dans 69,8 % des cas. Une ou plusieurs déchirures iatrogènes ont été notées chez 11,8 % des patients. Concernant le tamponnement interne, il a été réalisé par gaz SF6 ou C2F6 chez 31,5 % des patients et par l’huile de silicone chez 23,8 % des patients. L’acuité visuelle postopératoire a été améliorée d’au moins 2 lignes chez 60 % de nos patients et l’HIV a récidivé chez 24,2 % de nos patients après la chirurgie.
Vitreous hemorrhage (VH) is the main complication of proliferative diabetic retinopathy and remains the primary indication for vitrectomy in diabetic patients. The objective of our study is to compare our medical and surgical management of VH with data from the literature and to report the functional results of our series. We studied a series of 284 cases collected over 2 years in two tertiary care centers. In our series, 90.1% of patients had type 2 diabetes, and 70% had glycosylated hemoglobin greater than 7.5%. On fundus examination, 35.2% presented with stage 1 VH, 42.6% with stage 2, 3.6% with stage 3 and 5.2% with stage 4. Ocular ultrasound performed when fundus exam was difficult diagnosed an associated tractional retinal detachment in 8.8% of patients. Medical treatment was sufficient in 77.8% of patients, while 22.2% of our patients underwent vitrectomy, argon laser endophotocoagulation and postoperative anti-VEGF injection. Peeling of tractional fibrovascular membranes and or associated epiretinal membranes was performed in 69.8% of cases. Iatrogenic tears were noted in 11.8% of patients. In this study, 31.5% of patients underwent intraocular gas tamponade, while 23.8% of cases underwent silicone oil tamponade. Postoperative visual acuity improved by at least 2 lines in 60% of our patients, and the VH recurred in 24.2% of cases after surgery.
Chronic ocular small vessel disease: An overview of diabetic retinopathy and its relationship with cardiovascular health
2023, American Heart Journal Plus: Cardiology Research and Practice
Diabetic retinopathy (DR) is a potentially blinding disease originating from small vessel damage in the retina in chronic hyperglycemic states. DR has a complex multi-pathway driven pathogenesis resulting in diabetic macular edema and retinal ischemia, the former being the most common cause of vision impairment in DR. Hypoxia induced cytokines stimulate vascular endothelial growth factor (VEGF) production and subsequent angiogenesis with resultant mechanical retinal damage over time. Anti-VEGF therapy is effective for the treatment of center-involving diabetic macular edema. There is evolving evidence showing the effectiveness of anti-VEGF as both adjuvant and monotherapy in the treatment of proliferative DR, however laser photocoagulation continues to remain the standard of care. DR in large cohort studies has been shown to be an independent risk factor for the development of cardiovascular disease and mortality. In addition, changes in retinal vascular caliber ratios may have implications for risk of macrovascular events with a gender discrepancy towards women.
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Diabetic retinopathy is a frequent microvascular complication of diabetes and a major cause of visual impairment. In advanced stages, the abnormal neovascularization can lead to fibrosis and subsequent tractional retinal detachment and blindness. The low bioavailability of the drugs at the target site imposed by the anatomic and physiologic barriers within the eye, requires long term treatments with frequent injections that often compromise patient’s compliance and increase the risk of developing more complications. In recent years, much effort has been put towards the development of new drug delivery platforms aiming to enhance their permeation, to prolong their retention time at the target site and to provide a sustained release with reduced toxicity and improved efficacy. This review provides an overview of the etiology and pathophysiology of diabetic retinopathy and current treatments. It addresses the specific challenges associated to the different ocular delivery routes and provides a critical review of the most recent developments made in the drug delivery field.
Rates of RNFL Thinning in Patients with Suspected or Confirmed Glaucoma Receiving Unilateral Intravitreal Injections for Exudative AMD
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This study evaluated whether the rate of retinal nerve fiber layer (RNFL) thinning is faster in eyes receiving intravitreal injections than in fellow uninjected eyes among patients suspected of having or confirmed to have glaucoma and exudative age-related macular degeneration (AMD).
Retrospective comparative cohort study.
Patients with a diagnosis of unilateral exudative AMD and confirmed to have or suspected of having glaucoma in both eyes receiving unilateral intravitreal injections were identified. Those with ≥3 RNFL optical coherence tomography scans and ≥6 injections were included in the study. Rates of RNFL thinning in the injected eye versus the uninjected eye were estimated using linear mixed models. The main outcome measurement was the differences in rates of RNFL thinning in the injected versus the fellow uninjected eye. The effects of postinjection elevation of intraocular pressure (IOP), injection frequency, and number of injections were also evaluated.
A total of 53 patients met the inclusion criteria, receiving 26.4 ± 15.9 intravitreal injections. The average rate of RNFL thinning in uninjected eyes was −0.620 μm/year (P = .029). Injected eyes had an additional incremental loss of −0.385 μm/year, but this value was not statistically significant (95% confidence interval [CI]: −1.147 to 0.379 μm/year; P = .324). Subgroup analysis with only glaucoma patients (n = 33) also demonstrated a nonsignificant effect of injections (−0.568 μm/year; 95% CI: −1.454 to 0.319 μm/year; P = .212). Postinjection IOP elevation, injection frequency, and total number of injections were not associated with faster RNFL loss.
Among exudative AMD patients with glaucoma or suspected of having glaucoma, the rate of RNFL thinning in eyes receiving intravitreal injections did not significantly differ from that of fellow uninjected eyes.
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View all citing articles on Scopus

Manuscript no. 2006-136.

Genentech did not sponsor this study.

Dr Avery has received consulting or advisory fees from the following pharmaceutical companies: Alcon, Eyetech/OSI, Pfizer, Genentech, QLT, and Neovista. Dr Pieramici has received research, consulting, or advisory fees from the following pharmaceutical companies: Eyetech, Genentech, QLT, and Neovista.

Supported in part by the California Retina Research Foundation, Santa Barbara, California.

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Original ArticleIntravitreal Bevacizumab (Avastin) in the Treatment of Proliferative Diabetic Retinopathy

Purpose

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Section snippets

Patients and Methods

Results

Discussion

Ophthalmology

Ophthalmology

J Mol Biol

Ophthalmology

The mode of development of the vascular system of the retina, with some observations on its significance for certain retinal diseases

Trans Ophthalmol Soc U K

Tumor angiogenesis: therapeutic implications

N Engl J Med

Vascular endothelial growth factor: basic science and clinical progress

Endocr Rev

The role of vascular endothelial growth factor in ocular health and disease

Retina

Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders

N Engl J Med

Vascular endothelial growth factor is sufficient to produce iris neovascularization and neovascular glaucoma in a nonhuman primate

Arch Ophthalmol

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

Arch Ophthalmol

Original Article
Intravitreal Bevacizumab (Avastin) in the Treatment of Proliferative Diabetic Retinopathy