INTRAVITREOUS RANIBIZUMAB FOR PERSISTENT MACULAR EDEMA IN RETINAL VEIN OCCLUSION UNRESPONSIVE TO BEVACIZUMAB Jennifer E. De Niro, MD,* Arthur D. Fu, MD,*† Robert N. Johnson, MD,*† H. Richard McDonald, MD,*† J. Michael Jumper, MD,*† Emmett Cunningham, MD, PhD,*† Brandon J. Lujan, MD*†
Purpose: To report successful treatment of persistent retinal edema associated with retinal vascular occlusion with ranibizumab after initial failure with bevacizumab intravitreal injections. Methods: A retrospective chart review of all patients undergoing treatment with intravitreal bevacizumab for retinal vascular occlusion was undertaken. Clinical features of patients who were switched to monthly ranibizumab because of persistent and/or worsening retinal edema despite multiple (six or more) monthly intravitreal bevacizumab injections were selected for review. The type of retinal vascular occlusion, age of the patient, visual acuity at each visit, number of intravitreal bevacizumab injections, optical coherence tomography findings at each visit, fluorescein angiography, and number of intravitreal ranibizumab injections with optical coherence tomography findings at each subsequent visit were recorded. Results: Six patients (five women and one man) were identified. Age ranged from 56 years to 74 years. Five had central retinal vein occlusion and one a branch retinal vein occlusion. All were treated with at least 6 sequential intravitreal bevacizumab injections (range, 6–13) before treatment with ranibizumab. All demonstrated an immediate and marked reduction in retinal edema that had not occurred with any of the previous treatments. The average central foveal thickness on optical coherence tomography was 592 mm before ranibizumab injection and 346 mm after the injection. Visual acuity improved in four of the six patients and was stable in the remaining two patients. Conclusion: Eyes of patients with persistent macular edema secondary to retinal vein occlusion despite bevacizumab may experience prompt improvement after initiation of intravitreal ranibizumab injections. RETINAL CASES & BRIEF REPORTS 7:220–224, 2013
From the *Department of Ophthalmology, California Pacific Medical Center, San Francisco, California; and †West Coast Retina Medical Group, San Francisco, California.
Multicentered clinical trials have demonstrated that ranibizumab and bevacizumab seem to have similar efficacies in the treatment of exudative age-related macular degeneration.2 However, the relative efficacy of these two agents in the treatment of retinal vascular occlusion (RVO) has not been determined. Because intravitreal levels of vascular endothelial growth factor (VEGF) in central retinal vein occlusion (CRVO) are the highest of those measured among all retinal vascular disease,3 patients with vein occlusions may need more robust VEGF inhibition. Herein, we present six patients
T
he US Food and Drug Administration approved ranibizumab for the treatment of macular edema following retinal vein occlusion in 2010. However, before the approval of ranibizumab, many clinicians used bevacizumab on the basis of its similar molecular specificity to ranibizumab and efficacy in the treatment of neovascular age-related macular degeneration.1 220
221
INTRAVITREOUS RANIBIZUMAB
with RVO who had rapid resolution of macular edema associated with ranibizumab after initial failure with multiple sequential bevacizumab injections.
injection, her CFT had decreased to 293 mm and her visual acuity improved to 20/25.
Results Methods A retrospective case review was performed among patients in a multiphysician retinal referral private practice. We selected all patients with the diagnosis of RVO who were switched to monthly ranibizumab because of persistent and/or worsening retinal edema at a 4-week follow-up interval despite a minimum of 6 previous monthly intravitreal bevacizumab injections. This represents approximately 3% of the patients treated for RVO in our practice. Data reviewed included type of RVO (including fluorescein angiographic assessment of ischemia), age, visual acuity at each visit, number of intravitreal bevacizumab injections, optical coherence tomography findings at each visit, and number of intravitreal ranibizumab injections with optical coherence tomography findings at each subsequent visit. All optical coherence tomography were performed with Zeiss Cirrus (Dublin, CA) unless otherwise specified.
Case Report A 68-year-old woman presented with “a wave” across the upper part of her right visual field of 6-week duration. On examination, visual acuity was 20/40 in her right eye and 20/20 in her left eye. Her intraocular pressure was 18 on the right and 17 on the left. The slitlamp examination of both eyes and the dilated fundus examination of the left eye were unremarkable. Right eye examination was remarkable for an inferotemporal branch retinal vein occlusion involving the macula. Optical coherence tomography showed cystoid macular edema with a central foveal thickness (CFT) of 586 mm. She had received no previous ocular treatment for this branch vein occlusion. The patient’s blood pressure was 180/70 mmHg and she was referred to her primary care doctor for initiation of antihypertensive medications. Her medical history was noteworthy for a remote history of thyroidectomy for thyroid cancer. Her medications included levothyroxine, atorvastatin, and prevacid. The patient elected to begin therapy with off-label intravitreal bevacizumab (1.25 mg in 0.05 mL), and received 11 injections (approximately every 4–6 weeks) (Table 1). She initially had a good response to bevacizumab, with her CFT decreasing to a nadir of 265 mm after 2 injections. However, the macular edema worsened after the second bevacizumab injection and continued to increase to a CFT of 732 mm after the 11th bevacizumab injection. During this treatment period, her visual acuity fluctuated between 20/25 and 20/40. After informed consent, the patient elected to attempt trial of ranibizumab 0.5 mg. Four weeks after the first Supported by Pacific Vision Foundation (J.E.D.N, A.D.F., R.N. J., H.R.McD., J.M.J., E.C., B.J.L.). The authors have no conflicts of interest to disclose. Reprint requests: Robert N. Johnson, MD, West Coast Retina, 185 Berry Street, Suite 130, San Francisco, CA 94107; e-mail: [email protected]
We identified five additional patients who were switched to ranibizumab injections because of persistent retinal edema from RVO despite multiple sequential bevacizumab injections. All five patients had central retinal vein occlusions. The baseline characteristics of all six patients (including Case 1) are shown in Table 2. All patients had been treated with at least 6 sequential monthly intravitreal bevacizumab injections (range, 6–13) before treatment with ranibizumab. All six patients had displayed unsatisfactory responses to bevacizumab injections. Three of the patients (Cases 1, 4, and 6) showed an initial response to bevacizumab but then experienced rebound macular edema in excess of that observed before treatment. Case 2 also responded initially to bevacizumab but subsequently had recurrence of macular edema close to pretreatment levels. Case 5 never responded to bevacizumab injections and experienced a dramatic worsening of CFT despite monthly injections. Case 3 required 4 intravitreal injections of bevacizumab before CFT improved modestly from baseline. We did not attempt to shorten the treatment interval or increase the dosage of bevacizumab, and no additional therapies were tried before switching to ranibizumab. Five of the six patients had undergone fluorescein angiography at their initial evaluation. All five patients had a nonischemic RVO. Based on other indicators, such as cotton wool spots, initial visual acuity, and extent of retinal hemorrhage, our judgment was that the sixth patient was also nonischemic. All patients experienced a substantial reduction in retinal edema once they were switched to monthly ranibizumab injections (Figure 1). The average CFT was 592 mm before ranibizumab treatment. The average CFT after ranibizumab treatment, taken from the first follow-up visit after initiation of monthly ranibizumab injections, was 346 mm. Visual acuity improved in four of the six patients and was stable in the remaining two patients. Case 2 experienced a dramatic reduction in retinal edema after one ranibizumab injection, with a decrease in CFT from 619 mm to 348 mm. Case 3 had a more modest reduction in retinal edema but started ranibizumab treatment with a pre-ranibizumab CFT of 276 mm, which is significantly less than in the other patients. Case 4 had an initial 8-week hiatus after the first ranibizumab injection and the CFT increased during this interval. However, four weeks after the second ranibizumab injection, there was a substantial
222
RETINAL CASES & BRIEF REPORTS´ 2013 VOLUME 7 NUMBER 3
Table 1. Comparison of the Visual Acuities and Central Macular Thickness of Case 1 at Initial Presentation with a Branch Retinal Vein Occlusion and after Receiving Intravitreal Bevacizumab and Ranibizumab. All Optical Coherence Tomography Were Performed with Zeiss Cirrus Unless Otherwise Specified Central Foveal Thickness (mm)
Snellen Visual Acuity
Date
586* 284* 265* 352* 589 585 561 505 463 644 646 732 293 290 293 361 329
20/40 20/25 20/25 20/25 20/40 20/40 20/40 20/32 20/25 20/40 20/32 20/32 20/25 20/20 20/20 20/20 20/20
August 30, 2010 October 23, 2010 October 21, 2010 November 18, 2010 January 06, 2011 February 7, 2011 March 21, 2011 April 20, 2011 May 19, 2011 July 14, 2011 August 30, 2011 October 17, 2011 November 17, 2011 December 15, 2011 January 12, 2012 February 23, 12 March 22, 2012
Initial presentation After bevacizumab 1 After bevacizumab 2 After bevacizumab 3 After bevacizumab 4 After bevacizumab 5 After bevacizumab 6 After bevacizumab 7 After bevacizumab 8 After bevacizumab 9 After bevacizumab 10 After bevacizumab 11 After ranibizumab 1 After ranibizumab 2 After ranibizumab 3 After ranibizumab 4† After ranibizumab 5
*Zeiss Stratus optical coherence tomography. †Argon laser photocoagulation of the macula performed on January 26, 2012.
reduction in CFT. This is shown in Figure 1. Case 5 showed a moderate response to ranibizumab treatment on the first follow-up month and a marked response on the second follow-up month. This patient was switched back to bevacizumab after 2 ranibizumab injections for insurance reasons; her CFT decreased further to 250 mm after one bevacizumab injection but then increased to 421 mm after the second bevacizumab injection (data not shown in Figure 1). Case 6 experienced a significant response to ranibizumab after 13 sequential bevacizumab injections. The length of follow-up after the switch to ranibizumab ranged from 11 months to 21 months (average 13 months). Five of the six patients continued to require monthly injections to control macular edema, suggesting a continued high-frequency treatment burden.
Discussion Bevacizumab is a full-length humanized immunoglobulin G antibody that was approved by the US Food and Drug Administration for the treatment of metastatic colorectal cancer in 2004. Ranibizumab is a humanized antigen-binding fragment that was designed specifically for intraocular injection and was initially approved by the US Food and Drug Administration for the treatment of choroidal neovascularization secondary to agerelated macular degeneration in 2006. Approval for the treatment of RVO was obtained in 2010. Ranibizumab is a smaller molecule (48 kDa) than bevacizumab (149 kDa).4 Ranibizumab may therefore penetrate the
retina more readily and may be cleared sooner systemically than bevacizumab. In a rabbit model, the vitreous half-life of ranibizumab is 2.9 days, compared with 4.3 days for bevacizumab.4 Both medications inhibit all isoforms of the VEGF-A molecule. However, ranibizumab has higher affinity for VEGF; on a molar basis, ranibizumab is 5 times to 20 times more potent that full length bevacizumab in bioassays measuring VEGFinduced endothelial cell mitogenesis.5 The greater affinity of ranibizumab for VEGF and its shorter halflife in the vitreous may translate into clinical differences between ranibizumab and bevacizumab. Results of the Comparison of Age-Related Macular Degeneration Treatment Trials (CATT) have shown lack of inferiority between the two medications in the treatment of age-related macular degeneration.2 Interestingly though, monthly ranibizumab in the CATT resulted in the greatest reduction of persistent macular edema, suggesting a greater clinical potency than monthly bevacizumab. Retinal vascular occlusion has been shown to create the highest VEGF levels of any measured retinal vascular disorder. Measurements of VEGF levels in the aqueous fluid of patients with CRVO averaged 9.0 ng/mL, compared with 5.5 ng/mL in patients with active proliferative diabetic retinopathy and 0.1 ng/mL in patients with nonproliferative diabetic retinopathy.3 The high VEGF burden of RVO could theoretically offer a treatment advantage to ranibizumab because of its greater affinity for VEGF. There are no randomized prospective trials comparing the two medications in the treatment of RVO. While ranibizumab was approved by the US Food and
223 *Elapsed time after first ranibizumab injection was 56 days. Twenty-eight days after the second ranibizumab injection, CFT had decreased to 202 mm and Snellen visual acuity had improved to 20/125.
293 348 236 705* 632 363 20/25 20/40 20/100 20/200 20/63 20/32 48 42 42 28 28 28 11 10 7 8 6 13 Right Left Right Left Left Right BVO CRVO CRVO CRVO CRVO CRVO 68 56 74 74 57 66 1 2 3 4 5 6
Female Female Male Female Female Female
Laterality Diagnosis Age Case
Sex
20/32 20/40 20/60 20/250 20/100 20/50
732 619 276 599 836 489
Central Foveal Thickness After First Ranibizumab Injection (mm) Snellen Visual Acuity After First Ranibizumab Injection Central Foveal Thickness Before Ranibizumab (mm) Previous Bevacizumab Injections
Snellen Visual Acuity Before Ranibizumab
Time Between Last Bevacizumab Injection and First Ranibizumab Injection (Days)
Table 2. Baseline Characteristics and Clinical Response to Ranibizumab of Patients with Persistent, Nonresponsive Retinal Edema from Retinal Vein Occlusions Despite Monthly Sequential Intravitreal Bevacizumab Injections. All Optical Coherence Tomography Were Performed with Zeiss Cirrus
INTRAVITREOUS RANIBIZUMAB
Fig. 1. Change in central foveal thickness after patients with refractory macular edema from vein occlusions were switched from bevacizumab to ranibizumab injections. The post-ranibizumab data are from the first follow-up visit with the exception of Case 4, whose initial follow-up visit occurred 56 days after the first ranibizumab injection. All optical coherence tomographies were performed with Zeiss Cirrus.
Drug Administration for the treatment of CRVOinduced macular edema in 2010, earlier reports suggested efficacy of bevacizumab treatment of macular edema complicating CRVO.6,7 There is some suggestion, however, that ranibizumab is more effective than bevacizumab in treating branch vein occlusion. A case report described a 74-year-old woman who experienced rapid resolution of macular edema associated with a CRVO from a single ranibizumab injection after failure with 7 sequential bevacizumab injections.8 Spaide et al9 reported a prospective case series of 20 patients given ranibizumab for CRVOassociated macular edema that included 11 patients who had received bevacizumab injections previously. Those 11 patients had received a median of 6 bevacizumab injections, with a median time of 58 days between the last bevacizumab injection and entry into the study. There was no difference in the visual acuity gain among those who had previous bevacizumab treatment versus those who were started on ranibizumab without previous treatment. Four of the six patients in our series experienced a worsening of macular edema after monthly bevacizumab injections beyond the pretreatment level of macular edema. Similarly, Matsumoto et al10 described three patients with macular edema secondary to RVO whose edema initially responded to intravitreal bevacizumab but subsequently recurred in excess of
224
RETINAL CASES & BRIEF REPORTS´ 2013 VOLUME 7 NUMBER 3
pretreatment levels. They hypothesized that inhibition of the VEGF pathway by bevacizumab may upregulate VEGF receptors in the retina. This phenomenon may explain the decrease in the duration of the treatment response to bevacizumab and could account for the increased benefit we observed with ranibizumab. This case series provides further evidence that those patients with unresolved macular edema from retinal vein occlusion after multiple sequential bevacizumab injections may benefit from treatment with ranibizumab. An important weakness of our study is that, because it was not randomized, selection bias may have occurred. Patients with insurance coverage that subsidized ranibizumab injections may have been more likely to be switched from bevacizumab to ranibizumab than other patients. Despite this limitation, our findings imply important potential differences between these two medications. Further study is needed to better delineate the relative effectiveness of ranibizumab versus bevacizumab. Key words: retinal vein occlusion, ranibizumab, bevacizumab. References 1. Bashshur ZF, Haddad ZA, Schakal A, et al. Intravitreal bevacizumab for the treatment of neovascular age-related macular degeneration: a one-year prospective study. Am J Ophthalmol 2008;145:249–256.
2. CATT Research Group, Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011;364:1897–1908. 3. Aiello LP, Avery RL, Arrigg PG, Keyt BA. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331:1480–1487. 4. Bakri SJ, Snyder MR, Reid JM, et al. Pharmacokinetics of intravitreal ranibizumab (Lucentis). Ophthalmology 2007;114: 2179–2182. 5. Ferrara N, Damico L, Shams N, et al. Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina 2006;26:859–870. 6. Rosenfeld PJ, Fung AE, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for macular edema from central retinal vein occlusion. Ophthalmic Surg Lasers Imaging 2005;36:336–339. 7. Wu L, Arevalo JF, Berrocal MH, et al. Comparison of two doses of intravitreal bevacizumab (Avastin) for treatment of macular edema secondary to branch retinal vein occlusion: results from the Pan-American Collaborative Retina Study Group at 6 months of follow-up. Retina 2008:212–219. 8. Labriola LT, Sadda SR. Rapid resolution of macular edema associated with central retinal vein occlusion using ranibizumab after failure with multiple bevacizumab injections. Semin Ophthalmol 2011;26:387–391. 9. Spaide RF, Chang LK, Klancnik JM, et al. Prospective study of Intravitreal ranibizumab as a treatment for decreased visual acuity secondary to central retinal vein occlusion. Am J Ophthalmol 2009;147:298–306. 10. Matsumoto Y, Freund KB, Peiretti E, Cooney MJ. Rebound macular edema following bevacizumab (Avastin) therapy for retinal venous occlusive disease. Retina 2007;27:426–431.
Purpose: To report successful treatment of persistent retinal edema associated with retinal vascular occlusion with ranibizumab after initial failure with bevacizumab intravitreal injections. Methods: A retrospective chart review of all patients undergoing treatment with intravitreal bevacizumab for retinal vascular occlusion was undertaken. Clinical features of patients who were switched to monthly ranibizumab because of persistent and/or worsening retinal edema despite multiple (six or more) monthly intravitreal bevacizumab injections were selected for review. The type of retinal vascular occlusion, age of the patient, visual acuity at each visit, number of intravitreal bevacizumab injections, optical coherence tomography findings at each visit, fluorescein angiography, and number of intravitreal ranibizumab injections with optical coherence tomography findings at each subsequent visit were recorded. Results: Six patients (five women and one man) were identified. Age ranged from 56 years to 74 years. Five had central retinal vein occlusion and one a branch retinal vein occlusion. All were treated with at least 6 sequential intravitreal bevacizumab injections (range, 6–13) before treatment with ranibizumab. All demonstrated an immediate and marked reduction in retinal edema that had not occurred with any of the previous treatments. The average central foveal thickness on optical coherence tomography was 592 mm before ranibizumab injection and 346 mm after the injection. Visual acuity improved in four of the six patients and was stable in the remaining two patients. Conclusion: Eyes of patients with persistent macular edema secondary to retinal vein occlusion despite bevacizumab may experience prompt improvement after initiation of intravitreal ranibizumab injections. RETINAL CASES & BRIEF REPORTS 7:220–224, 2013
From the *Department of Ophthalmology, California Pacific Medical Center, San Francisco, California; and †West Coast Retina Medical Group, San Francisco, California.
Multicentered clinical trials have demonstrated that ranibizumab and bevacizumab seem to have similar efficacies in the treatment of exudative age-related macular degeneration.2 However, the relative efficacy of these two agents in the treatment of retinal vascular occlusion (RVO) has not been determined. Because intravitreal levels of vascular endothelial growth factor (VEGF) in central retinal vein occlusion (CRVO) are the highest of those measured among all retinal vascular disease,3 patients with vein occlusions may need more robust VEGF inhibition. Herein, we present six patients
T
he US Food and Drug Administration approved ranibizumab for the treatment of macular edema following retinal vein occlusion in 2010. However, before the approval of ranibizumab, many clinicians used bevacizumab on the basis of its similar molecular specificity to ranibizumab and efficacy in the treatment of neovascular age-related macular degeneration.1 220
221
INTRAVITREOUS RANIBIZUMAB
with RVO who had rapid resolution of macular edema associated with ranibizumab after initial failure with multiple sequential bevacizumab injections.
injection, her CFT had decreased to 293 mm and her visual acuity improved to 20/25.
Results Methods A retrospective case review was performed among patients in a multiphysician retinal referral private practice. We selected all patients with the diagnosis of RVO who were switched to monthly ranibizumab because of persistent and/or worsening retinal edema at a 4-week follow-up interval despite a minimum of 6 previous monthly intravitreal bevacizumab injections. This represents approximately 3% of the patients treated for RVO in our practice. Data reviewed included type of RVO (including fluorescein angiographic assessment of ischemia), age, visual acuity at each visit, number of intravitreal bevacizumab injections, optical coherence tomography findings at each visit, and number of intravitreal ranibizumab injections with optical coherence tomography findings at each subsequent visit. All optical coherence tomography were performed with Zeiss Cirrus (Dublin, CA) unless otherwise specified.
Case Report A 68-year-old woman presented with “a wave” across the upper part of her right visual field of 6-week duration. On examination, visual acuity was 20/40 in her right eye and 20/20 in her left eye. Her intraocular pressure was 18 on the right and 17 on the left. The slitlamp examination of both eyes and the dilated fundus examination of the left eye were unremarkable. Right eye examination was remarkable for an inferotemporal branch retinal vein occlusion involving the macula. Optical coherence tomography showed cystoid macular edema with a central foveal thickness (CFT) of 586 mm. She had received no previous ocular treatment for this branch vein occlusion. The patient’s blood pressure was 180/70 mmHg and she was referred to her primary care doctor for initiation of antihypertensive medications. Her medical history was noteworthy for a remote history of thyroidectomy for thyroid cancer. Her medications included levothyroxine, atorvastatin, and prevacid. The patient elected to begin therapy with off-label intravitreal bevacizumab (1.25 mg in 0.05 mL), and received 11 injections (approximately every 4–6 weeks) (Table 1). She initially had a good response to bevacizumab, with her CFT decreasing to a nadir of 265 mm after 2 injections. However, the macular edema worsened after the second bevacizumab injection and continued to increase to a CFT of 732 mm after the 11th bevacizumab injection. During this treatment period, her visual acuity fluctuated between 20/25 and 20/40. After informed consent, the patient elected to attempt trial of ranibizumab 0.5 mg. Four weeks after the first Supported by Pacific Vision Foundation (J.E.D.N, A.D.F., R.N. J., H.R.McD., J.M.J., E.C., B.J.L.). The authors have no conflicts of interest to disclose. Reprint requests: Robert N. Johnson, MD, West Coast Retina, 185 Berry Street, Suite 130, San Francisco, CA 94107; e-mail: [email protected]
We identified five additional patients who were switched to ranibizumab injections because of persistent retinal edema from RVO despite multiple sequential bevacizumab injections. All five patients had central retinal vein occlusions. The baseline characteristics of all six patients (including Case 1) are shown in Table 2. All patients had been treated with at least 6 sequential monthly intravitreal bevacizumab injections (range, 6–13) before treatment with ranibizumab. All six patients had displayed unsatisfactory responses to bevacizumab injections. Three of the patients (Cases 1, 4, and 6) showed an initial response to bevacizumab but then experienced rebound macular edema in excess of that observed before treatment. Case 2 also responded initially to bevacizumab but subsequently had recurrence of macular edema close to pretreatment levels. Case 5 never responded to bevacizumab injections and experienced a dramatic worsening of CFT despite monthly injections. Case 3 required 4 intravitreal injections of bevacizumab before CFT improved modestly from baseline. We did not attempt to shorten the treatment interval or increase the dosage of bevacizumab, and no additional therapies were tried before switching to ranibizumab. Five of the six patients had undergone fluorescein angiography at their initial evaluation. All five patients had a nonischemic RVO. Based on other indicators, such as cotton wool spots, initial visual acuity, and extent of retinal hemorrhage, our judgment was that the sixth patient was also nonischemic. All patients experienced a substantial reduction in retinal edema once they were switched to monthly ranibizumab injections (Figure 1). The average CFT was 592 mm before ranibizumab treatment. The average CFT after ranibizumab treatment, taken from the first follow-up visit after initiation of monthly ranibizumab injections, was 346 mm. Visual acuity improved in four of the six patients and was stable in the remaining two patients. Case 2 experienced a dramatic reduction in retinal edema after one ranibizumab injection, with a decrease in CFT from 619 mm to 348 mm. Case 3 had a more modest reduction in retinal edema but started ranibizumab treatment with a pre-ranibizumab CFT of 276 mm, which is significantly less than in the other patients. Case 4 had an initial 8-week hiatus after the first ranibizumab injection and the CFT increased during this interval. However, four weeks after the second ranibizumab injection, there was a substantial
222
RETINAL CASES & BRIEF REPORTS´ 2013 VOLUME 7 NUMBER 3
Table 1. Comparison of the Visual Acuities and Central Macular Thickness of Case 1 at Initial Presentation with a Branch Retinal Vein Occlusion and after Receiving Intravitreal Bevacizumab and Ranibizumab. All Optical Coherence Tomography Were Performed with Zeiss Cirrus Unless Otherwise Specified Central Foveal Thickness (mm)
Snellen Visual Acuity
Date
586* 284* 265* 352* 589 585 561 505 463 644 646 732 293 290 293 361 329
20/40 20/25 20/25 20/25 20/40 20/40 20/40 20/32 20/25 20/40 20/32 20/32 20/25 20/20 20/20 20/20 20/20
August 30, 2010 October 23, 2010 October 21, 2010 November 18, 2010 January 06, 2011 February 7, 2011 March 21, 2011 April 20, 2011 May 19, 2011 July 14, 2011 August 30, 2011 October 17, 2011 November 17, 2011 December 15, 2011 January 12, 2012 February 23, 12 March 22, 2012
Initial presentation After bevacizumab 1 After bevacizumab 2 After bevacizumab 3 After bevacizumab 4 After bevacizumab 5 After bevacizumab 6 After bevacizumab 7 After bevacizumab 8 After bevacizumab 9 After bevacizumab 10 After bevacizumab 11 After ranibizumab 1 After ranibizumab 2 After ranibizumab 3 After ranibizumab 4† After ranibizumab 5
*Zeiss Stratus optical coherence tomography. †Argon laser photocoagulation of the macula performed on January 26, 2012.
reduction in CFT. This is shown in Figure 1. Case 5 showed a moderate response to ranibizumab treatment on the first follow-up month and a marked response on the second follow-up month. This patient was switched back to bevacizumab after 2 ranibizumab injections for insurance reasons; her CFT decreased further to 250 mm after one bevacizumab injection but then increased to 421 mm after the second bevacizumab injection (data not shown in Figure 1). Case 6 experienced a significant response to ranibizumab after 13 sequential bevacizumab injections. The length of follow-up after the switch to ranibizumab ranged from 11 months to 21 months (average 13 months). Five of the six patients continued to require monthly injections to control macular edema, suggesting a continued high-frequency treatment burden.
Discussion Bevacizumab is a full-length humanized immunoglobulin G antibody that was approved by the US Food and Drug Administration for the treatment of metastatic colorectal cancer in 2004. Ranibizumab is a humanized antigen-binding fragment that was designed specifically for intraocular injection and was initially approved by the US Food and Drug Administration for the treatment of choroidal neovascularization secondary to agerelated macular degeneration in 2006. Approval for the treatment of RVO was obtained in 2010. Ranibizumab is a smaller molecule (48 kDa) than bevacizumab (149 kDa).4 Ranibizumab may therefore penetrate the
retina more readily and may be cleared sooner systemically than bevacizumab. In a rabbit model, the vitreous half-life of ranibizumab is 2.9 days, compared with 4.3 days for bevacizumab.4 Both medications inhibit all isoforms of the VEGF-A molecule. However, ranibizumab has higher affinity for VEGF; on a molar basis, ranibizumab is 5 times to 20 times more potent that full length bevacizumab in bioassays measuring VEGFinduced endothelial cell mitogenesis.5 The greater affinity of ranibizumab for VEGF and its shorter halflife in the vitreous may translate into clinical differences between ranibizumab and bevacizumab. Results of the Comparison of Age-Related Macular Degeneration Treatment Trials (CATT) have shown lack of inferiority between the two medications in the treatment of age-related macular degeneration.2 Interestingly though, monthly ranibizumab in the CATT resulted in the greatest reduction of persistent macular edema, suggesting a greater clinical potency than monthly bevacizumab. Retinal vascular occlusion has been shown to create the highest VEGF levels of any measured retinal vascular disorder. Measurements of VEGF levels in the aqueous fluid of patients with CRVO averaged 9.0 ng/mL, compared with 5.5 ng/mL in patients with active proliferative diabetic retinopathy and 0.1 ng/mL in patients with nonproliferative diabetic retinopathy.3 The high VEGF burden of RVO could theoretically offer a treatment advantage to ranibizumab because of its greater affinity for VEGF. There are no randomized prospective trials comparing the two medications in the treatment of RVO. While ranibizumab was approved by the US Food and
223 *Elapsed time after first ranibizumab injection was 56 days. Twenty-eight days after the second ranibizumab injection, CFT had decreased to 202 mm and Snellen visual acuity had improved to 20/125.
293 348 236 705* 632 363 20/25 20/40 20/100 20/200 20/63 20/32 48 42 42 28 28 28 11 10 7 8 6 13 Right Left Right Left Left Right BVO CRVO CRVO CRVO CRVO CRVO 68 56 74 74 57 66 1 2 3 4 5 6
Female Female Male Female Female Female
Laterality Diagnosis Age Case
Sex
20/32 20/40 20/60 20/250 20/100 20/50
732 619 276 599 836 489
Central Foveal Thickness After First Ranibizumab Injection (mm) Snellen Visual Acuity After First Ranibizumab Injection Central Foveal Thickness Before Ranibizumab (mm) Previous Bevacizumab Injections
Snellen Visual Acuity Before Ranibizumab
Time Between Last Bevacizumab Injection and First Ranibizumab Injection (Days)
Table 2. Baseline Characteristics and Clinical Response to Ranibizumab of Patients with Persistent, Nonresponsive Retinal Edema from Retinal Vein Occlusions Despite Monthly Sequential Intravitreal Bevacizumab Injections. All Optical Coherence Tomography Were Performed with Zeiss Cirrus
INTRAVITREOUS RANIBIZUMAB
Fig. 1. Change in central foveal thickness after patients with refractory macular edema from vein occlusions were switched from bevacizumab to ranibizumab injections. The post-ranibizumab data are from the first follow-up visit with the exception of Case 4, whose initial follow-up visit occurred 56 days after the first ranibizumab injection. All optical coherence tomographies were performed with Zeiss Cirrus.
Drug Administration for the treatment of CRVOinduced macular edema in 2010, earlier reports suggested efficacy of bevacizumab treatment of macular edema complicating CRVO.6,7 There is some suggestion, however, that ranibizumab is more effective than bevacizumab in treating branch vein occlusion. A case report described a 74-year-old woman who experienced rapid resolution of macular edema associated with a CRVO from a single ranibizumab injection after failure with 7 sequential bevacizumab injections.8 Spaide et al9 reported a prospective case series of 20 patients given ranibizumab for CRVOassociated macular edema that included 11 patients who had received bevacizumab injections previously. Those 11 patients had received a median of 6 bevacizumab injections, with a median time of 58 days between the last bevacizumab injection and entry into the study. There was no difference in the visual acuity gain among those who had previous bevacizumab treatment versus those who were started on ranibizumab without previous treatment. Four of the six patients in our series experienced a worsening of macular edema after monthly bevacizumab injections beyond the pretreatment level of macular edema. Similarly, Matsumoto et al10 described three patients with macular edema secondary to RVO whose edema initially responded to intravitreal bevacizumab but subsequently recurred in excess of
224
RETINAL CASES & BRIEF REPORTS´ 2013 VOLUME 7 NUMBER 3
pretreatment levels. They hypothesized that inhibition of the VEGF pathway by bevacizumab may upregulate VEGF receptors in the retina. This phenomenon may explain the decrease in the duration of the treatment response to bevacizumab and could account for the increased benefit we observed with ranibizumab. This case series provides further evidence that those patients with unresolved macular edema from retinal vein occlusion after multiple sequential bevacizumab injections may benefit from treatment with ranibizumab. An important weakness of our study is that, because it was not randomized, selection bias may have occurred. Patients with insurance coverage that subsidized ranibizumab injections may have been more likely to be switched from bevacizumab to ranibizumab than other patients. Despite this limitation, our findings imply important potential differences between these two medications. Further study is needed to better delineate the relative effectiveness of ranibizumab versus bevacizumab. Key words: retinal vein occlusion, ranibizumab, bevacizumab. References 1. Bashshur ZF, Haddad ZA, Schakal A, et al. Intravitreal bevacizumab for the treatment of neovascular age-related macular degeneration: a one-year prospective study. Am J Ophthalmol 2008;145:249–256.
2. CATT Research Group, Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011;364:1897–1908. 3. Aiello LP, Avery RL, Arrigg PG, Keyt BA. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331:1480–1487. 4. Bakri SJ, Snyder MR, Reid JM, et al. Pharmacokinetics of intravitreal ranibizumab (Lucentis). Ophthalmology 2007;114: 2179–2182. 5. Ferrara N, Damico L, Shams N, et al. Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina 2006;26:859–870. 6. Rosenfeld PJ, Fung AE, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for macular edema from central retinal vein occlusion. Ophthalmic Surg Lasers Imaging 2005;36:336–339. 7. Wu L, Arevalo JF, Berrocal MH, et al. Comparison of two doses of intravitreal bevacizumab (Avastin) for treatment of macular edema secondary to branch retinal vein occlusion: results from the Pan-American Collaborative Retina Study Group at 6 months of follow-up. Retina 2008:212–219. 8. Labriola LT, Sadda SR. Rapid resolution of macular edema associated with central retinal vein occlusion using ranibizumab after failure with multiple bevacizumab injections. Semin Ophthalmol 2011;26:387–391. 9. Spaide RF, Chang LK, Klancnik JM, et al. Prospective study of Intravitreal ranibizumab as a treatment for decreased visual acuity secondary to central retinal vein occlusion. Am J Ophthalmol 2009;147:298–306. 10. Matsumoto Y, Freund KB, Peiretti E, Cooney MJ. Rebound macular edema following bevacizumab (Avastin) therapy for retinal venous occlusive disease. Retina 2007;27:426–431.
