Short-Term Response of Macular Oedema to Intravitreal Bevacizumab
Short-Term Response of Macular Oedema to Intravitreal Bevacizumab
Background/aims: Bevacizumab has been shown to be an effective treatment of macular oedema. This study assesses the response of macular oedema to bevacizumab with specific focus on the first 24 h postinjection.
Methods: Subjects with diabetic macular oedema (DMO) or exudative age-related macular degeneration (ARMD) received intravitreal bevacizumab injections. Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity and OCT macular thickness measurements were obtained at baseline, 1, 3, 6, 24 and 48 h, 1 week and 1 month postinjection.
Results: The average baseline OCT was 452.91 µm (SD 182.96, range 249.00 to 784.00). After injection, there was a statistically significant decrease in OCT thickness within 2 h with a plateau phase out to 24 h, followed by a significant drop between 24 and 48 h, and a return towards baseline between 1 week and 1 month. Average changes in ETDRS visual acuity were not statistically significant, though many patients experienced a positive outcome.
Conclusion: While there is an immediate pressure-related effect, it appears that the anti-VEGF effects of bevacizumab require approximately 24 h to become active and persist for 2-3 weeks. These results suggest that injections at 2-3-week intervals might provide improved clinical outcomes, compared with the currently typical 4-6-week interval of injections.
The leading causes of blindness in the USA are retinal and choroidal diseases, which are correlated to neovascularisation and excessive vascular permeability in the retina. One of the underlying causes of these vascular changes is the activity of an isoform of vascular endothelial growth factor (VEGF) called VEGF-A. It can increase the permeability of macular blood vessels through various mechanisms, including leucocyte-mediated endothelial injury, fenestrae formation, dissolution of tight junctions and transcellular bulk flow. The breakdown of the blood-retinal barrier can lead to macular oedema, defined as a central retinal thickness exceeding 300 μm. Besides these important physiological effects, VEGF-A is a potent angiogenic stimulant leading to new blood-vessel formation. It has been clearly linked to many angiogenic diseases, including diabetic retinopathy, retinal vein occlusion, iris neovascularisation, retinopathy of prematurity, age-related macular degeneration, corneal neovascularisation and diabetic macular oedema.
With the increasing prevalence of diabetes worldwide, DMO has emerged as a significant cause of vision loss and morbidity. DMO affects approximately 28-29% of patients within 20 years of onset of type 1 or type 2 diabetes. Traditional treatments for DMO include focal argon laser photocoagulation and intravitreal triamcinolone acetonide. In light of the role of neovascularisation and vascular permeability in macular oedema, combined with the complications associated with conventional treatments, anti-VEGF drugs are also being employed to help restore vision in DMO patients. One drug which appears promising in this regard is bevacizumab. Currently, bevacizumab is approved for the treatment of various cancers, though its effectiveness in treating macular oedema is being intensively studied. Like other intravitreal VEGF inhibitors such as ranibizumab and pegaptanib sodium, bevacizumab is an antibody which binds and inhibits VEGF-A.
Bevacizumab provides unique advantages over the currently available VEGF-A inhibitors. VEGF-A itself exists in a number of different isoforms, all of which can be bound by bevacizumab. This is in contrast to pegaptanib sodium, which only binds the VEGF165 isoform of VEGF-A. Additionally, a single antibody molecule of bevacizumab contains two VEGF-A binding sites. This indicates that bevacizumab could be a more effective VEGF-A inhibitor than the other anti-VEGF drugs per molecule of antibody administered. However, other characteristics prove disadvantageous for the use of bevacizumab. For example, bevacizumab is a full-length antibody molecule, while ranibizumab is a half antibody molecule. This is significant, since antibody fragments have been shown to penetrate further into the retina than full antibodies. Still, other evidence shows that bevacizumab can achieve full retinal penetration within 24 h of injection. While bevacizumab shows significant potential as a treatment for diabetic macular oedema, further studies are necessary to validate its efficacy.
Optical coherence tomography (OCT) imaging has provided the ability to image microscopic structures within the body. Using low-coherence interferometry, this technique allows for two-dimensional cross-sectional imaging of internal organ structures. This imaging modality has, thus, been especially useful for imaging intraocular structures including the retina and its associated vasculature. Moreover, the efficacy of bevacizumab and other anti-angiogenic drugs has been evaluated quantitatively using OCT imaging. In those clinical studies, the patients had vision loss from ARMD or DMO. Using OCT imaging, the thicknesses of the patients’ retinas were measured before and after injection of bevacizumab. The OCT measurements showed a significant decrease in the thickness of the retina 1 week and 4 weeks after treatment. These results have provided evidence that bevacizumab could successfully reduce macular oedema from ARMD and DMO and, further, maintain these results over many weeks.
While these studies demonstrated the effectiveness of bevacizumab over 1-6 weeks, it remains unknown how this treatment affects macular oedema over shorter time periods. Anecdotal reports of patients treated for macular oedema using anti-VEGF agents have indicated that these patients experienced symptomatic improvements within the first 24 h following treatment. In light of these observations, we have monitored the efficacy of bevacizumab over the course of hours rather than weeks. By doing so, we now report the rate and pattern of the changes in OCT thickness and visual acuity.
Abstract and Introduction
Abstract
Background/aims: Bevacizumab has been shown to be an effective treatment of macular oedema. This study assesses the response of macular oedema to bevacizumab with specific focus on the first 24 h postinjection.
Methods: Subjects with diabetic macular oedema (DMO) or exudative age-related macular degeneration (ARMD) received intravitreal bevacizumab injections. Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity and OCT macular thickness measurements were obtained at baseline, 1, 3, 6, 24 and 48 h, 1 week and 1 month postinjection.
Results: The average baseline OCT was 452.91 µm (SD 182.96, range 249.00 to 784.00). After injection, there was a statistically significant decrease in OCT thickness within 2 h with a plateau phase out to 24 h, followed by a significant drop between 24 and 48 h, and a return towards baseline between 1 week and 1 month. Average changes in ETDRS visual acuity were not statistically significant, though many patients experienced a positive outcome.
Conclusion: While there is an immediate pressure-related effect, it appears that the anti-VEGF effects of bevacizumab require approximately 24 h to become active and persist for 2-3 weeks. These results suggest that injections at 2-3-week intervals might provide improved clinical outcomes, compared with the currently typical 4-6-week interval of injections.
Introduction
The leading causes of blindness in the USA are retinal and choroidal diseases, which are correlated to neovascularisation and excessive vascular permeability in the retina. One of the underlying causes of these vascular changes is the activity of an isoform of vascular endothelial growth factor (VEGF) called VEGF-A. It can increase the permeability of macular blood vessels through various mechanisms, including leucocyte-mediated endothelial injury, fenestrae formation, dissolution of tight junctions and transcellular bulk flow. The breakdown of the blood-retinal barrier can lead to macular oedema, defined as a central retinal thickness exceeding 300 μm. Besides these important physiological effects, VEGF-A is a potent angiogenic stimulant leading to new blood-vessel formation. It has been clearly linked to many angiogenic diseases, including diabetic retinopathy, retinal vein occlusion, iris neovascularisation, retinopathy of prematurity, age-related macular degeneration, corneal neovascularisation and diabetic macular oedema.
With the increasing prevalence of diabetes worldwide, DMO has emerged as a significant cause of vision loss and morbidity. DMO affects approximately 28-29% of patients within 20 years of onset of type 1 or type 2 diabetes. Traditional treatments for DMO include focal argon laser photocoagulation and intravitreal triamcinolone acetonide. In light of the role of neovascularisation and vascular permeability in macular oedema, combined with the complications associated with conventional treatments, anti-VEGF drugs are also being employed to help restore vision in DMO patients. One drug which appears promising in this regard is bevacizumab. Currently, bevacizumab is approved for the treatment of various cancers, though its effectiveness in treating macular oedema is being intensively studied. Like other intravitreal VEGF inhibitors such as ranibizumab and pegaptanib sodium, bevacizumab is an antibody which binds and inhibits VEGF-A.
Bevacizumab provides unique advantages over the currently available VEGF-A inhibitors. VEGF-A itself exists in a number of different isoforms, all of which can be bound by bevacizumab. This is in contrast to pegaptanib sodium, which only binds the VEGF165 isoform of VEGF-A. Additionally, a single antibody molecule of bevacizumab contains two VEGF-A binding sites. This indicates that bevacizumab could be a more effective VEGF-A inhibitor than the other anti-VEGF drugs per molecule of antibody administered. However, other characteristics prove disadvantageous for the use of bevacizumab. For example, bevacizumab is a full-length antibody molecule, while ranibizumab is a half antibody molecule. This is significant, since antibody fragments have been shown to penetrate further into the retina than full antibodies. Still, other evidence shows that bevacizumab can achieve full retinal penetration within 24 h of injection. While bevacizumab shows significant potential as a treatment for diabetic macular oedema, further studies are necessary to validate its efficacy.
Optical coherence tomography (OCT) imaging has provided the ability to image microscopic structures within the body. Using low-coherence interferometry, this technique allows for two-dimensional cross-sectional imaging of internal organ structures. This imaging modality has, thus, been especially useful for imaging intraocular structures including the retina and its associated vasculature. Moreover, the efficacy of bevacizumab and other anti-angiogenic drugs has been evaluated quantitatively using OCT imaging. In those clinical studies, the patients had vision loss from ARMD or DMO. Using OCT imaging, the thicknesses of the patients’ retinas were measured before and after injection of bevacizumab. The OCT measurements showed a significant decrease in the thickness of the retina 1 week and 4 weeks after treatment. These results have provided evidence that bevacizumab could successfully reduce macular oedema from ARMD and DMO and, further, maintain these results over many weeks.
While these studies demonstrated the effectiveness of bevacizumab over 1-6 weeks, it remains unknown how this treatment affects macular oedema over shorter time periods. Anecdotal reports of patients treated for macular oedema using anti-VEGF agents have indicated that these patients experienced symptomatic improvements within the first 24 h following treatment. In light of these observations, we have monitored the efficacy of bevacizumab over the course of hours rather than weeks. By doing so, we now report the rate and pattern of the changes in OCT thickness and visual acuity.
