Ranibizumab With and Without Ketorolac Eyedrops for AMD
Ranibizumab With and Without Ketorolac Eyedrops for AMD
The results of this prospective study suggest that the addition of topical 0.45% ketorolac may produce a significant reduction of CMT in patients with CNV treated by intravitreal ranibizumab. These findings are in agreement with the results of previous experimental studies in rats, in which topical ketorolac significantly inhibited CNV by suppressing retinal PGE2 and VEGF expression.
Although the pathogenesis of CNV is multifactorial and complex, the process begins with damage to the outer retinal cells and retinal pigment epithelium, which triggers a cascade of inflammatory and angiogenic responses leading to neovascularisation deep beneath the macula. The introduction of anti-VEGF drugs for CNV has markedly improved control of the disease, as studies with bevacizumab and ranibizumab have shown. However, greater benefits may be achieved if angiogenesis, scarring and inflammation are targeted simultaneously.
There is convincing evidence that cyclooxygenase (COX) plays an important role in promoting the angiogenesis involved in CNV. COX catalyses the biosynthesis of eicosanoids from membrane-derived arachidonic acid to produce thromboxanes and prostaglandins, which are involved in the development of CNV. In vitro studies have shown that PGE2 increases the expression of VEGF in cultured rat Müller cells. Kim et al have demonstrated that topical and intravitreal ketorolac significantly reduce angiographic leakage and retinal levels of PGE2 and VEGF in an animal model of CNV.
Ketorolac is a potent NSAID that inhibits COX and is used to treat ocular inflammation and pain after cataract surgery. Several lines of evidence also support its use for posterior segment inflammation, since therapeutic concentrations (2.8 nm/mL) of ketorolac are found in the vitreous following topical administration. Patients treated with ketorolac had significantly lower PGE2 levels than untreated controls. In laser-induced CNV in rats, ketorolac reduced retinal PGE2 expression by 35% and retinal VEGF expression by 31% at 3 days; moreover, CNV was reduced by 27% at 2 weeks when assessed by fluorescein angiography.
Our findings demonstrate that topical ketorolac acts in conjunction with intravitreal anti-VEGF treatment. CMT reduction was significantly higher (−37.1 μm) in patients receiving combination treatment (Table 2 and figure 2), although there were no differences in either visual acuity or number of injections between the two groups. This finding is in contrast with the findings of a recent study by Gomi et al, in which the authors reported a reduction in the frequency of ranibizumab injections over 6 months when topical bromfenac was used as an adjunctive treatment with ranibizumab. However, in addition to the differences in the pharmacological properties of bromfenac and ketorolac, another point of difference was that Gomi et al administered just one ranibizumab injection and then treated the patients on an as-needed basis; these differences may have caused the significant difference in the number of injections required. Moreover, they recruited eyes with thinner CMT than those noted in our study (365±62 vs 417±87.7 in the combination groups). Our results are consistent with the results of another recently published trial evaluating the use of topical bromfenac in combination with ranibizumab. A significantly greater reduction in CMT was found after 12 months in the combination group (−28.3% vs −18.9%), without concomitant differences in visual acuity changes between the two arms.
The visual acuity improvements that we observed in both groups were in line with those reported in published studies and, as has been previously noted, changed non-linearly with CMT.
Although a significant difference in the improvement of visual acuity was not detectable between the groups after 6 months, a greater CMT reduction was appreciable in group 1 as soon as 2 months after the beginning of treatment. A thinner initial CMT is associated with greater photoreceptor integrity after resolution of exudation, and more severe exudative changes during the acute phase of CNV might cause more retinal damage and inner segment/outer segment (IS/OS) disruption. Thus, less retinal fluid and disruption of retinal architecture in the combination group may provide a better opportunity for preservation or improvement of vision over the longer term, as well as a reduction in the frequency of anti-VEGF injections.
Topical administration of ketorolac has many advantages over intravitreal treatment, namely, better safety, lower costs and easier handling. However, some adverse effects related to topical NSAID administration, including corneal toxicity, have been reported. Importantly, greater risks such as retinal detachment, endophthalmitis, retinal toxicity and other ocular injuries have been associated with intravitreal drug administration, even though the achievable ketorolac concentration in the posterior chamber is higher than that after topical treatment. In our study, we decided to administer ketorolac three times a day to obtain the best effect/compliance ratio.
In this study, we did not observe any adverse events related to topical ketorolac administration, and compliance with eyedrop use appeared very high. No statistically significant difference in ocular symptoms was observed between the two treatment arms.
To the best of our knowledge, this is the first open-label pilot study investigating the efficacy and safety of a combination of 0.45% ketorolac eyedrops three times a day and standard ranibizumab intravitreal injections in patients affected by CNV. However, our study has a few limitations. First, the sample size was small, although it provided a power of approximately 0.75 for demonstrating an effect size d of 0.72 between the two groups (t test, two-sided α level of 5%). Second, the study period was rather short, although results for ranibizumab treatment have been reported after a 6-month period.
In conclusion, this pilot study suggests that topical 0.45% ketorolac administered three times a day acts additively with intravitreal ranibizumab to reduce CMT in CNV. It is important to evaluate the long-term efficacy of NSAIDs, as AMD is a chronic disease with an inflammatory component. In particular, careful attention should be paid to the corneal complications associated with long-term use of topical NSAIDs.
Discussion
The results of this prospective study suggest that the addition of topical 0.45% ketorolac may produce a significant reduction of CMT in patients with CNV treated by intravitreal ranibizumab. These findings are in agreement with the results of previous experimental studies in rats, in which topical ketorolac significantly inhibited CNV by suppressing retinal PGE2 and VEGF expression.
Although the pathogenesis of CNV is multifactorial and complex, the process begins with damage to the outer retinal cells and retinal pigment epithelium, which triggers a cascade of inflammatory and angiogenic responses leading to neovascularisation deep beneath the macula. The introduction of anti-VEGF drugs for CNV has markedly improved control of the disease, as studies with bevacizumab and ranibizumab have shown. However, greater benefits may be achieved if angiogenesis, scarring and inflammation are targeted simultaneously.
There is convincing evidence that cyclooxygenase (COX) plays an important role in promoting the angiogenesis involved in CNV. COX catalyses the biosynthesis of eicosanoids from membrane-derived arachidonic acid to produce thromboxanes and prostaglandins, which are involved in the development of CNV. In vitro studies have shown that PGE2 increases the expression of VEGF in cultured rat Müller cells. Kim et al have demonstrated that topical and intravitreal ketorolac significantly reduce angiographic leakage and retinal levels of PGE2 and VEGF in an animal model of CNV.
Ketorolac is a potent NSAID that inhibits COX and is used to treat ocular inflammation and pain after cataract surgery. Several lines of evidence also support its use for posterior segment inflammation, since therapeutic concentrations (2.8 nm/mL) of ketorolac are found in the vitreous following topical administration. Patients treated with ketorolac had significantly lower PGE2 levels than untreated controls. In laser-induced CNV in rats, ketorolac reduced retinal PGE2 expression by 35% and retinal VEGF expression by 31% at 3 days; moreover, CNV was reduced by 27% at 2 weeks when assessed by fluorescein angiography.
Our findings demonstrate that topical ketorolac acts in conjunction with intravitreal anti-VEGF treatment. CMT reduction was significantly higher (−37.1 μm) in patients receiving combination treatment (Table 2 and figure 2), although there were no differences in either visual acuity or number of injections between the two groups. This finding is in contrast with the findings of a recent study by Gomi et al, in which the authors reported a reduction in the frequency of ranibizumab injections over 6 months when topical bromfenac was used as an adjunctive treatment with ranibizumab. However, in addition to the differences in the pharmacological properties of bromfenac and ketorolac, another point of difference was that Gomi et al administered just one ranibizumab injection and then treated the patients on an as-needed basis; these differences may have caused the significant difference in the number of injections required. Moreover, they recruited eyes with thinner CMT than those noted in our study (365±62 vs 417±87.7 in the combination groups). Our results are consistent with the results of another recently published trial evaluating the use of topical bromfenac in combination with ranibizumab. A significantly greater reduction in CMT was found after 12 months in the combination group (−28.3% vs −18.9%), without concomitant differences in visual acuity changes between the two arms.
The visual acuity improvements that we observed in both groups were in line with those reported in published studies and, as has been previously noted, changed non-linearly with CMT.
Although a significant difference in the improvement of visual acuity was not detectable between the groups after 6 months, a greater CMT reduction was appreciable in group 1 as soon as 2 months after the beginning of treatment. A thinner initial CMT is associated with greater photoreceptor integrity after resolution of exudation, and more severe exudative changes during the acute phase of CNV might cause more retinal damage and inner segment/outer segment (IS/OS) disruption. Thus, less retinal fluid and disruption of retinal architecture in the combination group may provide a better opportunity for preservation or improvement of vision over the longer term, as well as a reduction in the frequency of anti-VEGF injections.
Topical administration of ketorolac has many advantages over intravitreal treatment, namely, better safety, lower costs and easier handling. However, some adverse effects related to topical NSAID administration, including corneal toxicity, have been reported. Importantly, greater risks such as retinal detachment, endophthalmitis, retinal toxicity and other ocular injuries have been associated with intravitreal drug administration, even though the achievable ketorolac concentration in the posterior chamber is higher than that after topical treatment. In our study, we decided to administer ketorolac three times a day to obtain the best effect/compliance ratio.
In this study, we did not observe any adverse events related to topical ketorolac administration, and compliance with eyedrop use appeared very high. No statistically significant difference in ocular symptoms was observed between the two treatment arms.
To the best of our knowledge, this is the first open-label pilot study investigating the efficacy and safety of a combination of 0.45% ketorolac eyedrops three times a day and standard ranibizumab intravitreal injections in patients affected by CNV. However, our study has a few limitations. First, the sample size was small, although it provided a power of approximately 0.75 for demonstrating an effect size d of 0.72 between the two groups (t test, two-sided α level of 5%). Second, the study period was rather short, although results for ranibizumab treatment have been reported after a 6-month period.
In conclusion, this pilot study suggests that topical 0.45% ketorolac administered three times a day acts additively with intravitreal ranibizumab to reduce CMT in CNV. It is important to evaluate the long-term efficacy of NSAIDs, as AMD is a chronic disease with an inflammatory component. In particular, careful attention should be paid to the corneal complications associated with long-term use of topical NSAIDs.