The Effect of Intravitreal Anti-VEGF Injections on IOP
The Effect of Intravitreal Anti-VEGF Injections on IOP
Hoang QV, Mendonca LS, Della Torre KE, Jung JJ, Tsuang AJ, Freund KB
Ophthalmology. 2012;119:321-326
Intravitreal ranibizumab and bevacizumab (Lucentis® and Avastin®, respectively; Genentech; San Francisco, California) are anti-vascular endothelial growth factor (anti-VEGF) agents that have revolutionized the treatment of neovascular age-related macular degeneration (AMD). Typically, 0.05 mL of these drugs are injected into the patient's vitreous cavity on a monthly basis. Adverse effects from the injections are rarely observed. Sustained ocular hypertension was not found to be a potential complication in the large trials of these anti-VEGF agents. Yet, in a post hoc analysis of the data from these trials, a greater likelihood that intraocular pressure (IOP) would increase from baseline (before injection) was found in patients who received anti-VEGF agents.
Hoang and colleagues' retrospective cohort study sought to address this concern. Medical records of 207 patients with neovascular AMD who presented to a single physician at a retinal referral practice in New York over a 6-month period were reviewed. Patients who had a baseline diagnosis of glaucoma with an IOP greater than 21 mm Hg on the first preinjection day were deemed not well controlled and excluded. Collected data included demographic information, total number of bevacizumab or ranibizumab injections received, and IOP at each visit. Only patients undergoing unilateral treatment were included, so the contralateral untreated eye served as the control.
The 207 patients were divided into 4 approximately equal-sized groups ( 48-57 eyes per group) according to the total number of injections the eyes had received. The number of injections for groups I, II, III, and IV were 3-12, 13-21, 22-28, and 29 or more, respectively. The main outcome measure was a pressure increase of more than 5 mm Hg from baseline on at least 2 consecutive visits.
The mean total number of injections was 20.8 (range, 3-48). On 2 or more consecutive visits, 11.6% of treated eyes and 5.3% of untreated eyes had IOP elevations of more than 5 mm Hg from baseline (P = .02). In the group of patients with elevated IOP, the mean total number of injections performed was 24.4 (95% confidence interval [CI], 20.9-28.0), whereas in the group of those without IOP elevation, the mean total number of injections was 20.4 (95% CI, 18.9-21.8). The odds ratio (5.75; 95% CI, 1.19-27.8; P = .03) of eyes experiencing an IOP elevation of more than 5 mm Hg on 2 or more consecutive visits was increased, compared with eyes receiving 12 or fewer injections.
In total, IOP-lowering intervention was started in 3 control eyes, whereas 13 eyes in the injection group were started on some treatment. Of the variables considered, only the total number of injections showed a statistically significant association with an IOP elevation of more than 5 mm Hg above baseline on 2 or more consecutive visits (P = .05).
This study is of high clinical value, given the number of patients who receive treatment for AMD with anti-VEGF agents. Previous research has revealed potential complications of these injections; however, a possibly common side effect, increased IOP, may have been overlooked and underemphasized thus far.
A transient increase in IOP, as a result of the addition of fluid into the posterior chamber, is expected immediately after an intravitreal injection. However, studies have shown that the IOP returns to less than 25 mm Hg, and close to baseline, within 30-60 minutes after injection without the use of IOP-lowering therapy. Therefore, if present, a sustained increase in IOP is probably not caused by the addition of volume alone, but by different mechanisms.
Case studies have reported sustained and delayed IOP elevations after intravitreal treatment with anti-VEGF agents, and Hoang and colleagues' findings also suggest that the risk for sustained ocular hypertension increases with cumulative injections. Sham injections used as controls in the MARINA and ANCHOR trials did not result in the same degree of IOP elevation, suggesting that the raised IOP cannot be attributed to an increase in intraocular volume. Proposed theories about the cause of ocular hypertension with administration of anti-VEGF agents include a pharmacologic effect, an inflammatory mechanism causing trabeculitis, or a physical blockade of the trabecular meshwork from protein aggregates or silicone droplet accumulation
If the mechanism of IOP elevation is physical obstruction of the trabecular network, the rates of IOP elevation between the 2 anti-VEGF agents might vary because of a difference in their molecular weights and sizes. This study did not perform a subset analysis according to the agent received. However, Good and colleagues found a slightly statistically significant difference in the rate of IOP elevation between the 2 agents, with more ocular hypertension occurring with bevacizumab, the larger molecule. Of interest, in this large-scale study examining persistent IOP elevation after anti-VEGF injection, patients with preexisting glaucoma had a higher prevalence of IOP elevation than those without glaucoma (33% vs 3.1%). Good and colleagues' study also looked for a correlation between patients who had sustained IOP increases and preexisting glaucoma, but the P value did not reach significance.
In conclusion, Hoang and colleagues' study provides more evidence for potential sustained ocular hypertension after repeated anti-VEGF injections. Although it seems logical that this is more likely to occur in patients with preexisting glaucoma, this study did not find such a correlation; therefore, all patients should be monitored. Moreover, it is unclear whether the risk is the same with ranibizumab and bevacizumab, but sustained ocular hypertension can occur with either agent. Therefore, ophthalmologists -- especially those who administer these agents -- should be aware of this potential side effect and be ready to treat it accordingly.
Abstract
Effect on Intraocular Pressure in Patients Receiving Unilateral Intravitreal Anti-Vascular Endothelial Growth Factor Injections
Hoang QV, Mendonca LS, Della Torre KE, Jung JJ, Tsuang AJ, Freund KB
Ophthalmology. 2012;119:321-326
Study Summary
Intravitreal ranibizumab and bevacizumab (Lucentis® and Avastin®, respectively; Genentech; San Francisco, California) are anti-vascular endothelial growth factor (anti-VEGF) agents that have revolutionized the treatment of neovascular age-related macular degeneration (AMD). Typically, 0.05 mL of these drugs are injected into the patient's vitreous cavity on a monthly basis. Adverse effects from the injections are rarely observed. Sustained ocular hypertension was not found to be a potential complication in the large trials of these anti-VEGF agents. Yet, in a post hoc analysis of the data from these trials, a greater likelihood that intraocular pressure (IOP) would increase from baseline (before injection) was found in patients who received anti-VEGF agents.
Hoang and colleagues' retrospective cohort study sought to address this concern. Medical records of 207 patients with neovascular AMD who presented to a single physician at a retinal referral practice in New York over a 6-month period were reviewed. Patients who had a baseline diagnosis of glaucoma with an IOP greater than 21 mm Hg on the first preinjection day were deemed not well controlled and excluded. Collected data included demographic information, total number of bevacizumab or ranibizumab injections received, and IOP at each visit. Only patients undergoing unilateral treatment were included, so the contralateral untreated eye served as the control.
The 207 patients were divided into 4 approximately equal-sized groups ( 48-57 eyes per group) according to the total number of injections the eyes had received. The number of injections for groups I, II, III, and IV were 3-12, 13-21, 22-28, and 29 or more, respectively. The main outcome measure was a pressure increase of more than 5 mm Hg from baseline on at least 2 consecutive visits.
The mean total number of injections was 20.8 (range, 3-48). On 2 or more consecutive visits, 11.6% of treated eyes and 5.3% of untreated eyes had IOP elevations of more than 5 mm Hg from baseline (P = .02). In the group of patients with elevated IOP, the mean total number of injections performed was 24.4 (95% confidence interval [CI], 20.9-28.0), whereas in the group of those without IOP elevation, the mean total number of injections was 20.4 (95% CI, 18.9-21.8). The odds ratio (5.75; 95% CI, 1.19-27.8; P = .03) of eyes experiencing an IOP elevation of more than 5 mm Hg on 2 or more consecutive visits was increased, compared with eyes receiving 12 or fewer injections.
In total, IOP-lowering intervention was started in 3 control eyes, whereas 13 eyes in the injection group were started on some treatment. Of the variables considered, only the total number of injections showed a statistically significant association with an IOP elevation of more than 5 mm Hg above baseline on 2 or more consecutive visits (P = .05).
Viewpoint
This study is of high clinical value, given the number of patients who receive treatment for AMD with anti-VEGF agents. Previous research has revealed potential complications of these injections; however, a possibly common side effect, increased IOP, may have been overlooked and underemphasized thus far.
A transient increase in IOP, as a result of the addition of fluid into the posterior chamber, is expected immediately after an intravitreal injection. However, studies have shown that the IOP returns to less than 25 mm Hg, and close to baseline, within 30-60 minutes after injection without the use of IOP-lowering therapy. Therefore, if present, a sustained increase in IOP is probably not caused by the addition of volume alone, but by different mechanisms.
Case studies have reported sustained and delayed IOP elevations after intravitreal treatment with anti-VEGF agents, and Hoang and colleagues' findings also suggest that the risk for sustained ocular hypertension increases with cumulative injections. Sham injections used as controls in the MARINA and ANCHOR trials did not result in the same degree of IOP elevation, suggesting that the raised IOP cannot be attributed to an increase in intraocular volume. Proposed theories about the cause of ocular hypertension with administration of anti-VEGF agents include a pharmacologic effect, an inflammatory mechanism causing trabeculitis, or a physical blockade of the trabecular meshwork from protein aggregates or silicone droplet accumulation
If the mechanism of IOP elevation is physical obstruction of the trabecular network, the rates of IOP elevation between the 2 anti-VEGF agents might vary because of a difference in their molecular weights and sizes. This study did not perform a subset analysis according to the agent received. However, Good and colleagues found a slightly statistically significant difference in the rate of IOP elevation between the 2 agents, with more ocular hypertension occurring with bevacizumab, the larger molecule. Of interest, in this large-scale study examining persistent IOP elevation after anti-VEGF injection, patients with preexisting glaucoma had a higher prevalence of IOP elevation than those without glaucoma (33% vs 3.1%). Good and colleagues' study also looked for a correlation between patients who had sustained IOP increases and preexisting glaucoma, but the P value did not reach significance.
In conclusion, Hoang and colleagues' study provides more evidence for potential sustained ocular hypertension after repeated anti-VEGF injections. Although it seems logical that this is more likely to occur in patients with preexisting glaucoma, this study did not find such a correlation; therefore, all patients should be monitored. Moreover, it is unclear whether the risk is the same with ranibizumab and bevacizumab, but sustained ocular hypertension can occur with either agent. Therefore, ophthalmologists -- especially those who administer these agents -- should be aware of this potential side effect and be ready to treat it accordingly.
Abstract
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