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Clinical and Experimental Ophthalmology 2015; 43: 803–807 doi: 10.1111/ceo.12559
Original Article Aflibercept for the treatment of neovascular glaucoma Jeffrey R SooHoo MD, Leonard K Seibold MD, Mina B Pantcheva MD and Malik Y Kahook MD Department of Ophthalmology, University of Colorado School of Medicine, Aurora, Colorado, USA
ABSTRACT Background: Neovascular glaucoma (NVG) is a potentially blinding disease associated with ocular ischaemia. Use of an anti-vascular endothelial growth factor agent has been reported as a treatment option for NVG. The purpose of this study was to investigate initial results regarding the treatment of NVG with intravitreal aflibercept. Design: This study employed a prospective, interventional case series study design. Participants: Patients with newly diagnosed stage 1 or 2 neovascular glaucoma were eligible to participate in this study. Methods: Four patients with newly diagnosed stage 1 or 2 NVG were treated with intravitreal aflibercept at the time of diagnosis, with planned repeat injection at 4 weeks, 8 weeks and then every 8 weeks thereafter up until 52 weeks after study initiation. Main Outcome Measures: Primary outcomes were regression of neovascularization of the iris and angle (NVI, NVA). Secondary outcome measurements included visual acuity and intraocular pressure (IOP). Results: Intravitreal aflibercept resulted in rapid regression of NVI and NVA. IOP was stable or reduced in all patients at the 52-week study visit.
Conclusions: These results suggest that intravitreal aflibercept may be an effective treatment for stage 1 and 2 NVG, resulting in rapid and sustained regression of NVI and NVA as well as control of IOP. Further research is needed to determine the full duration of effect and the optimal dose and timing of administration. Key words: glaucoma, intraocular pressure, neovascularization, vascular endothelial growth factor.
INTRODUCTION Aflibercept (Eylea, Regeneron, New York; Bayer, Berlin, Germany) is a recombinant fusion protein that binds to and inhibits vascular endothelial growth factor (VEGF) and placental growth factor (PlGF).1 Aflibercept is a potent inhibitor of VEGF due to its superior binding affinity and pharmacokinetics compared to earlier anti-VEGF molecules.2,3 These characteristics could lead to a prolonged duration of clinical effect compared to other anti-VEGF agents. In 2011, the United States Food and Drug Administration approved aflibercept for the treatment of neovascular age-related macular degeneration (AMD). It has been shown that neovascular AMD and neovascular glaucoma (NVG) are both associated with increased expression of VEGF.4–7 NVG is typically classified in stages of 0–3. In stages 1 and 2, abnormal vessel proliferation is seen with or without elevated intraocular pressure (IOP), but the anterior chamber angle is still open. In stage 3 NVG, fibrovascular contraction leads to the
■ Correspondence: Dr Malik Y Kahook, Department of Ophthalmology, University of Colorado School of Medicine, 1675 Aurora Ct Mail Stop F-731, Aurora, CO 80045, USA. Email: [email protected] Received 18 February 2015; accepted 21 May 2015. Conflict of interest: Dr Kahook received an unrestricted research grant from Regeneron to conduct this study. Funding sources: This study was supported by an unrestricted research grant from Regeneron. © 2015 Royal Australian and New Zealand College of Ophthalmologists
804
SooHoo et al.
formation of peripheral anterior synechiae and subsequent secondary angle closure glaucoma. Targeting patients for anti-VEGF treatment prior to the development of angle closure may lead to regression of neovascularization of the iris and angle (NVI, NVA). If formation of a fibrovascular membrane covering the trabecular meshwork is prevented or reversed, the conventional outflow pathways may maintain or recover normal function and allow for IOP to remain stable at or return to physiologic levels. The ischemic drive that leads to formation of abnormal vessels in NVG is typically treated with panretinal photocoagulation (PRP). PRP is often effective and leads to regression of NVI and NVA. However, destruction of the retina leads to permanent visual dysfunction.8 Anti-VEGF agents have been explored as a potential therapeutic adjunct or alternative to PRP in patients with NVG.9–12 The use of intravitreal bevacizumab has been show to result in regression of NVI and NVA and normalization of IOP.13,14 IOP control can improve patient comfort and allow one to delay or even avoid more invasive glaucoma surgery. To our knowledge, the use of aflibercept in NVG has not been reported in peerreviewed literature. Aflibercept’s potential for longer efficacy and its combined approach against VEGF and PlGF might lead to enhanced outcomes compared to previously investigated anti-neovascular therapeutic approaches in NVG, as VEGF and PlGF have been shown to act synergistically in pathologic angiogenesis.15 In this prospective, consecutive case series, we report initial results regarding use of intravitreal aflibercept in the treatment of stage 1 and 2 NVG.
eligible for rescue PRP if anti-VEGF therapy alone failed to control their neovascular disease and IOP.
RESULTS Case 1 A 71-year-old woman presented for follow-up of a branch retinal artery occlusion of the left eye diagnosed 1 month previously. She had a history of mild non-proliferative diabetic retinopathy without prior ocular surgery, laser or injections. Visual acuity was 20/200 and IOP was 29 mmHg. Slit lamp examination and gonioscopy revealed both NVI and NVA. NVI was confirmed with iris fluorescein angiography (Fig. 1). The fellow eye demonstrated no evidence of neovascularization. Intravitreal injection of aflibercept was performed. By 1 week after injection, IOP had improved to 21 mmHg. The NVI was completely resolved (Fig. 2), as was the NVA. The patient was started on dorzolamide twice daily in the left eye for an IOP of 24 mmHg at the week 16 visit. At last follow-up (52 weeks after initial injection), the patient had received eight injections of aflibercept with no recurrence of NVI/NVA. The patient’s vision remained 20/200 (secondary to macular ischemia) and her IOP was 19 mmHg on the same dose of dorzolamide.
Case 2 A 58-year-old diabetic woman presented with approximately 2 weeks of unilateral, painless vision loss of the left eye. Visual acuity was counting fingers and IOP was 17 mmHg. Slit lamp exam revealed early NVI encroaching on the anterior chamber
METHODS Prior to study initiation, the Colorado Multiple Institutional Review Board approved the study protocol (ClinicalTrials.gov #NCT01711879). Patients with newly diagnosed stage 1 or 2 NVG were evaluated for possible study inclusion. Informed consent was obtained prior to study enrollment. Patients underwent a full ophthalmic examination including measurement of visual acuity, IOP by applanation tonometry, slit lamp examination with gonioscopy, dilated fundus examination and iris and fundus fluorescein angiography, unless contraindicated. Using standard aseptic technique, all patients received an injection of intravitreal aflibercept (2 mg) on the day of study enrollment. At follow-up, patients received additional injections at 4 weeks, 8 weeks and at 8-week intervals thereafter throughout the duration of the study (52 weeks total). Visual acuity, IOP and the presence or absence of NVI and NVA were recorded at each visit. If necessary, patients were
Figure 1. Slit lamp photograph of the left eye of patient 1 at study enrollment. Iris fluorescein angiography demonstrates florid iris neovascularization.
© 2015 Royal Australian and New Zealand College of Ophthalmologists
Aflibercept and neovascular glaucoma
805 her left eye. The patient had missed the week 16 visit and refused treatment at the week 24 visit. Given the lack of recurrence of NVI or NVA, it was decided not to perform aflibercept injections at the subsequent follow-up visits. Visual acuity at week 52 was 20/32 in her left eye, with an IOP of 15 on latanoprost once daily, having been able to be weaned off the additional anti-glaucoma medications that were started upon presentation.
Case 4
Figure 2. Slit lamp photograph of the left eye of patient 1 one week after treatment with intravitreal aflibercept. Iris fluorescein angiography shows marked regression of the previously noted iris neovascularization.
angle. Dilated fundus exam was significant for proliferative diabetic retinopathy and chorioretinal scarring consistent with prior PRP. Neither NVI nor NVA were present in the fellow eye. The patient received an intravitreal injection of aflibercept in the left eye upon study enrollment. Examination the following day showed resolution of iris neovascularization. At last follow-up (52 weeks after initial injection), the patient had received eight injections of aflibercept with no recurrence of NVI/ NVA. Vision improved to 20/100 and IOP was 13 mmHg on no medications.
Case 3 A 76-year-old woman presented for routine follow-up of primary open angle glaucoma on latanoprost daily in both eyes. Vision was stable compared to her last visit at 20/30 in the right eye and 20/25 in the left eye. Applanation tonometry, however, revealed asymmetric IOP of 16 mmHg in the right eye and 34 mmHg in the left eye. Gonioscopy revealed 6 h of NVA in the left eye with a small hyphema. The etiology of her neovascularization remains unclear; although she has a history of diabetes, the remainder of her exam was not consistent with proliferative diabetic retinopathy. Examination of the right eye did not reveal any neovascularization. The patient underwent intravitreal aflibercept injection to the left eye as well as escalation of topical glaucoma medications; her IOP improved to 13 mmHg with stable vision one day later. By 1 week, the NVA had regressed so that only 1 h remained. At last follow-up (52 weeks after initial injection), she had received three injections in
A 40-year-old man presented to clinic complaining of a gradual decrease in vision in the left eye over the past month. His visual acuity was 20/60 and IOP was 14 mmHg. Slit lamp examination and gonioscopy revealed florid NVI and 3 h of NVA. Dilated fundus exam showed findings consistent with proliferative diabetic retinopathy, although the patient had not previously been diagnosed with diabetes. The patient received an injection of intravitreal aflibercept. By 1 week after injection, the NVA had resolved and the NVI had regressed to only 3 h remaining. At the 52-week visit, the patient’s vision had improved to 20/20, IOP was 14 mmHg on no medications, and the NVI and NVA had completely resolved. Over the study period, the patient received a total of eight injections of aflibercept. Further workup confirmed a suspected diagnosis of type 2 diabetes mellitus, and the patient was referred for primary care evaluation and management.
DISCUSSION These findings support the use of intravitreal aflibercept to reverse NVI and NVA as well as to control IOP in patients with NVG. Traditionally, PRP has been the gold standard treatment for NVG. Photocoagulation results in cellular destruction, reducing the hypoxic drive that results in upregulation of VEGF. By destroying ischemic tissue, VEGF production is mitigated, leading to regression of NVI and NVA.16,17 PRP does have adverse side effects, resulting in permanent visual field defects as well as reduced color vision and contrast sensitivity.8 Treatment with intravitreal anti-VEGF agents more directly addresses the pathophysiologic mechanism of ocular neovascularization by targeting the action of VEGF alone, thereby limiting and reversing the neovascular drive. Enthusiasm for treating NVG with anti-VEGF agents is tempered due to the necessity for repeated injections to maintain therapeutic outcomes. Patients in our study received ongoing injections at an initial interval of 4 weeks for the first three injections; subsequently, the interval was increased to 8 weeks. Patients were eligible for treatment with PRP or
© 2015 Royal Australian and New Zealand College of Ophthalmologists
806
SooHoo et al.
surgical intervention at the discretion of the treating physician. However, no patient required additional intervention during the 52-week study period. Intervals between injections were chosen based on established treatment protocols for neovascular AMD. It is possible, of course, that the optimal dosing interval for treatment of NVG is different. Further study is needed to investigate this possibility. The need for repeated anti-VEGF injections could be negated by the development of drug depots that can release medication at pre-specified intervals and doses. Possible approaches include poly(lactic-coglycolic)acid (PLGA) microspheres containing antiVEGF drug18 or a refillable mini drug pump.19 Longer term follow-up may also reveal that a ‘treat and extend’ approach, such as that used in the treatment of neovascular AMD,20,21 is a viable option in the management of NVG. Newer anti-VEGF agents or combination therapies that have more than one mechanism of action might also have a longer duration of action and allow for a longer interval between injections. Models of neovascular disease suggest that anti-VEGF therapy combined with an anti-platelet-derived growth factor agent more effectively reduces neovascularization compared to anti-VEGF treatment alone.22–24 Even if invasive filtration surgery is indicated to control IOP in NVG, pretreatment with an antiVEGF agent can reduce the risk of perioperative hyphema and improve IOP control in the postoperative period.25 Anti-VEGF treatment leads to more rapid regression of neovascularization than PRP and is therefore a more appropriate therapy prior to surgical treatment of NVG, especially if surgery is indicated urgently. Our findings show that intravitreal aflibercept may be a valid treatment option for NVG that is diagnosed prior to the development of synechial angle closure. Treatment with aflibercept can reverse NVI and NVA in early stages of NVG as well as stabilize or lower IOP. Limitations of this study include the small sample size and the fact that this was an open-label study without a matched group of control subjects. Our preliminary success suggests that aflibercept has the potential to delay or avoid the need for surgical treatment of NVG, if treatment is started early in the disease course. If surgery is indicated, treatment to induce regression of NVI and NVA may lower the risk of adverse events perioperatively and postoperatively. The optimal interval between treatments remains unclear and may need to be addressed on an individual or pro re nata basis. Further prospective studies are needed in larger cohorts of patients to better elucidate the clinical effects of aflibercept in NVG. Combination therapy with multiple agents, agents with multiple mechanisms of action and/or
extended release depots of anti-neovascular medications may further improve the utility and success of these treatments in the future.
ACKNOWLEDGEMENTS The authors would like to acknowledge the efforts of the University of Colorado retina service in performing the intravitreal injections and those of Naresh Mandava, MD (University of Colorado, Department of Ophthalmology) for acting as our internal medical monitor for this study.
REFERENCES 1. Ohr M, Kaiser PK. Intravitreal aflibercept injection for neovascular (wet) age-related macular degeneration. Expert Opin Pharmacother 2012; 13: 585–91. 2. Holash J, Davis S, Papadopoulos N et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A 2002; 99: 11393–8. 3. Papadopoulos N, Martin J, Ruan Q et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis 2012; 15: 171–85. 4. Adamis AP, Miller JW, Bernal MT et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol 1994; 118: 445–50. 5. Aiello LP, Avery RL, Arrigg PG et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994; 331: 1480–7. 6. Kvanta A, Algvere PV, Berglin L, Seregard S. Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor. Invest Ophthalmol Vis Sci 1996; 37: 1929– 34. 7. Lopez PF, Sippy BD, Lambert HM, Thach AB, Hinton DR. Transdifferentiated retinal pigment epithelial cells are immunoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes. Invest Ophthalmol Vis Sci 1996; 37: 855–68. 8. Fong DS, Girach A, Boney A. Visual side effects of successful scatter laser photocoagulation surgery for proliferative diabetic retinopathy: a literature review. Retina 2007; 27: 816–24. 9. Kahook MY, Schuman JS, Noecker RJ. Intravitreal bevacizumab in a patient with neovascular glaucoma. Ophthalmic Surg Lasers Imaging 2006; 37: 144–6. 10. Iliev ME, Domig D, Wolf-Schnurrbursch U, Wolf S, Sarra GM. Intravitreal bevacizumab (Avastin) in the treatment of neovascular glaucoma. Am J Ophthalmol 2006; 142: 1054–6. 11. Grisanti S, Biester S, Peters S, Tatar O, Ziemssen F, Bartz-Schmidt KU. Intracameral bevacizumab for iris rubeosis. Am J Ophthalmol 2006; 142: 158–60.
© 2015 Royal Australian and New Zealand College of Ophthalmologists
Aflibercept and neovascular glaucoma 12. Mason JO 3rd, Albert MA Jr, Mays A, Vail R. Regression of neovascular iris vessels by intravitreal injection of bevacizumab. Retina 2006; 26: 839–41. 13. Yazdani S, Hendi K, Pakravan M, Mahdavi M, Yaseri M. Intravitreal bevacizumab for neovascular glaucoma: a randomized controlled trial. J Glaucoma 2009; 18: 632–7. 14. Wakabayashi T, Oshima Y, Sakaguchi H et al. Intravitreal bevacizumab to treat iris neovascularization and neovascular glaucoma secondary to ischemic retinal diseases in 41 consecutive cases. Ophthalmology 2008; 115: 1571–80, 1580 e1571–3. 15. Carmeliet P, Moons L, Luttun A et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 2001; 7: 575–83. 16. Murphy RP, Egbert PR. Regression of iris neovascularization following panretinal photocoagulation. Arch Ophthalmol 1979; 97: 700–2. 17. Wand M, Dueker DK, Aiello LM, Grant WM. Effects of panretinal photocoagulation on rubeosis iridis, angle neovascularization, and neovascular glaucoma. Am J Ophthalmol 1978; 86: 332–9. 18. Carrasquillo KG, Ricker JA, Rigas IK, Miller JW, Gragoudas ES, Adamis AP. Controlled delivery of the anti-VEGF aptamer EYE001 with poly(lactic-coglycolic)acid microspheres. Invest Ophthalmol Vis Sci 2003; 44: 290–9. 19. Saati S, Lo R, Li PY, Meng E, Varma R, Humayun MS. Mini drug pump for ophthalmic use. Curr Eye Res 2010; 35: 192–201.
807 20. Gupta OP, Shienbaum G, Patel AH, Fecarotta C, Kaiser RS, Regillo CD. A treat and extend regimen using ranibizumab for neovascular age-related macular degeneration clinical and economic impact. Ophthalmology 2010; 117: 2134–40. 21. Shienbaum G, Gupta OP, Fecarotta C, Patel AH, Kaiser RS, Regillo CD. Bevacizumab for neovascular agerelated macular degeneration using a treat-and-extend regimen: clinical and economic impact. Am J Ophthalmol 2012; 153: 468–73, e461. 22. Jo N, Mailhos C, Ju M et al. Inhibition of plateletderived growth factor B signaling enhances the efficacy of anti-vascular endothelial growth factor therapy in multiple models of ocular neovascularization. Am J Pathol 2006; 168: 2036–53. 23. Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 2003; 111: 1287–95. 24. Erber R, Thurnher A, Katsen AD et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericytemediated endothelial cell survival mechanisms. FASEB J 2004; 18: 338–40. 25. Takihara Y, Inatani M, Kawaji T et al. Combined intravitreal bevacizumab and trabeculectomy with mitomycin C versus trabeculectomy with mitomycin C alone for neovascular glaucoma. J Glaucoma 2011; 20: 196–201.
© 2015 Royal Australian and New Zealand College of Ophthalmologists
Clinical and Experimental Ophthalmology 2015; 43: 803–807 doi: 10.1111/ceo.12559
Original Article Aflibercept for the treatment of neovascular glaucoma Jeffrey R SooHoo MD, Leonard K Seibold MD, Mina B Pantcheva MD and Malik Y Kahook MD Department of Ophthalmology, University of Colorado School of Medicine, Aurora, Colorado, USA
ABSTRACT Background: Neovascular glaucoma (NVG) is a potentially blinding disease associated with ocular ischaemia. Use of an anti-vascular endothelial growth factor agent has been reported as a treatment option for NVG. The purpose of this study was to investigate initial results regarding the treatment of NVG with intravitreal aflibercept. Design: This study employed a prospective, interventional case series study design. Participants: Patients with newly diagnosed stage 1 or 2 neovascular glaucoma were eligible to participate in this study. Methods: Four patients with newly diagnosed stage 1 or 2 NVG were treated with intravitreal aflibercept at the time of diagnosis, with planned repeat injection at 4 weeks, 8 weeks and then every 8 weeks thereafter up until 52 weeks after study initiation. Main Outcome Measures: Primary outcomes were regression of neovascularization of the iris and angle (NVI, NVA). Secondary outcome measurements included visual acuity and intraocular pressure (IOP). Results: Intravitreal aflibercept resulted in rapid regression of NVI and NVA. IOP was stable or reduced in all patients at the 52-week study visit.
Conclusions: These results suggest that intravitreal aflibercept may be an effective treatment for stage 1 and 2 NVG, resulting in rapid and sustained regression of NVI and NVA as well as control of IOP. Further research is needed to determine the full duration of effect and the optimal dose and timing of administration. Key words: glaucoma, intraocular pressure, neovascularization, vascular endothelial growth factor.
INTRODUCTION Aflibercept (Eylea, Regeneron, New York; Bayer, Berlin, Germany) is a recombinant fusion protein that binds to and inhibits vascular endothelial growth factor (VEGF) and placental growth factor (PlGF).1 Aflibercept is a potent inhibitor of VEGF due to its superior binding affinity and pharmacokinetics compared to earlier anti-VEGF molecules.2,3 These characteristics could lead to a prolonged duration of clinical effect compared to other anti-VEGF agents. In 2011, the United States Food and Drug Administration approved aflibercept for the treatment of neovascular age-related macular degeneration (AMD). It has been shown that neovascular AMD and neovascular glaucoma (NVG) are both associated with increased expression of VEGF.4–7 NVG is typically classified in stages of 0–3. In stages 1 and 2, abnormal vessel proliferation is seen with or without elevated intraocular pressure (IOP), but the anterior chamber angle is still open. In stage 3 NVG, fibrovascular contraction leads to the
■ Correspondence: Dr Malik Y Kahook, Department of Ophthalmology, University of Colorado School of Medicine, 1675 Aurora Ct Mail Stop F-731, Aurora, CO 80045, USA. Email: [email protected] Received 18 February 2015; accepted 21 May 2015. Conflict of interest: Dr Kahook received an unrestricted research grant from Regeneron to conduct this study. Funding sources: This study was supported by an unrestricted research grant from Regeneron. © 2015 Royal Australian and New Zealand College of Ophthalmologists
804
SooHoo et al.
formation of peripheral anterior synechiae and subsequent secondary angle closure glaucoma. Targeting patients for anti-VEGF treatment prior to the development of angle closure may lead to regression of neovascularization of the iris and angle (NVI, NVA). If formation of a fibrovascular membrane covering the trabecular meshwork is prevented or reversed, the conventional outflow pathways may maintain or recover normal function and allow for IOP to remain stable at or return to physiologic levels. The ischemic drive that leads to formation of abnormal vessels in NVG is typically treated with panretinal photocoagulation (PRP). PRP is often effective and leads to regression of NVI and NVA. However, destruction of the retina leads to permanent visual dysfunction.8 Anti-VEGF agents have been explored as a potential therapeutic adjunct or alternative to PRP in patients with NVG.9–12 The use of intravitreal bevacizumab has been show to result in regression of NVI and NVA and normalization of IOP.13,14 IOP control can improve patient comfort and allow one to delay or even avoid more invasive glaucoma surgery. To our knowledge, the use of aflibercept in NVG has not been reported in peerreviewed literature. Aflibercept’s potential for longer efficacy and its combined approach against VEGF and PlGF might lead to enhanced outcomes compared to previously investigated anti-neovascular therapeutic approaches in NVG, as VEGF and PlGF have been shown to act synergistically in pathologic angiogenesis.15 In this prospective, consecutive case series, we report initial results regarding use of intravitreal aflibercept in the treatment of stage 1 and 2 NVG.
eligible for rescue PRP if anti-VEGF therapy alone failed to control their neovascular disease and IOP.
RESULTS Case 1 A 71-year-old woman presented for follow-up of a branch retinal artery occlusion of the left eye diagnosed 1 month previously. She had a history of mild non-proliferative diabetic retinopathy without prior ocular surgery, laser or injections. Visual acuity was 20/200 and IOP was 29 mmHg. Slit lamp examination and gonioscopy revealed both NVI and NVA. NVI was confirmed with iris fluorescein angiography (Fig. 1). The fellow eye demonstrated no evidence of neovascularization. Intravitreal injection of aflibercept was performed. By 1 week after injection, IOP had improved to 21 mmHg. The NVI was completely resolved (Fig. 2), as was the NVA. The patient was started on dorzolamide twice daily in the left eye for an IOP of 24 mmHg at the week 16 visit. At last follow-up (52 weeks after initial injection), the patient had received eight injections of aflibercept with no recurrence of NVI/NVA. The patient’s vision remained 20/200 (secondary to macular ischemia) and her IOP was 19 mmHg on the same dose of dorzolamide.
Case 2 A 58-year-old diabetic woman presented with approximately 2 weeks of unilateral, painless vision loss of the left eye. Visual acuity was counting fingers and IOP was 17 mmHg. Slit lamp exam revealed early NVI encroaching on the anterior chamber
METHODS Prior to study initiation, the Colorado Multiple Institutional Review Board approved the study protocol (ClinicalTrials.gov #NCT01711879). Patients with newly diagnosed stage 1 or 2 NVG were evaluated for possible study inclusion. Informed consent was obtained prior to study enrollment. Patients underwent a full ophthalmic examination including measurement of visual acuity, IOP by applanation tonometry, slit lamp examination with gonioscopy, dilated fundus examination and iris and fundus fluorescein angiography, unless contraindicated. Using standard aseptic technique, all patients received an injection of intravitreal aflibercept (2 mg) on the day of study enrollment. At follow-up, patients received additional injections at 4 weeks, 8 weeks and at 8-week intervals thereafter throughout the duration of the study (52 weeks total). Visual acuity, IOP and the presence or absence of NVI and NVA were recorded at each visit. If necessary, patients were
Figure 1. Slit lamp photograph of the left eye of patient 1 at study enrollment. Iris fluorescein angiography demonstrates florid iris neovascularization.
© 2015 Royal Australian and New Zealand College of Ophthalmologists
Aflibercept and neovascular glaucoma
805 her left eye. The patient had missed the week 16 visit and refused treatment at the week 24 visit. Given the lack of recurrence of NVI or NVA, it was decided not to perform aflibercept injections at the subsequent follow-up visits. Visual acuity at week 52 was 20/32 in her left eye, with an IOP of 15 on latanoprost once daily, having been able to be weaned off the additional anti-glaucoma medications that were started upon presentation.
Case 4
Figure 2. Slit lamp photograph of the left eye of patient 1 one week after treatment with intravitreal aflibercept. Iris fluorescein angiography shows marked regression of the previously noted iris neovascularization.
angle. Dilated fundus exam was significant for proliferative diabetic retinopathy and chorioretinal scarring consistent with prior PRP. Neither NVI nor NVA were present in the fellow eye. The patient received an intravitreal injection of aflibercept in the left eye upon study enrollment. Examination the following day showed resolution of iris neovascularization. At last follow-up (52 weeks after initial injection), the patient had received eight injections of aflibercept with no recurrence of NVI/ NVA. Vision improved to 20/100 and IOP was 13 mmHg on no medications.
Case 3 A 76-year-old woman presented for routine follow-up of primary open angle glaucoma on latanoprost daily in both eyes. Vision was stable compared to her last visit at 20/30 in the right eye and 20/25 in the left eye. Applanation tonometry, however, revealed asymmetric IOP of 16 mmHg in the right eye and 34 mmHg in the left eye. Gonioscopy revealed 6 h of NVA in the left eye with a small hyphema. The etiology of her neovascularization remains unclear; although she has a history of diabetes, the remainder of her exam was not consistent with proliferative diabetic retinopathy. Examination of the right eye did not reveal any neovascularization. The patient underwent intravitreal aflibercept injection to the left eye as well as escalation of topical glaucoma medications; her IOP improved to 13 mmHg with stable vision one day later. By 1 week, the NVA had regressed so that only 1 h remained. At last follow-up (52 weeks after initial injection), she had received three injections in
A 40-year-old man presented to clinic complaining of a gradual decrease in vision in the left eye over the past month. His visual acuity was 20/60 and IOP was 14 mmHg. Slit lamp examination and gonioscopy revealed florid NVI and 3 h of NVA. Dilated fundus exam showed findings consistent with proliferative diabetic retinopathy, although the patient had not previously been diagnosed with diabetes. The patient received an injection of intravitreal aflibercept. By 1 week after injection, the NVA had resolved and the NVI had regressed to only 3 h remaining. At the 52-week visit, the patient’s vision had improved to 20/20, IOP was 14 mmHg on no medications, and the NVI and NVA had completely resolved. Over the study period, the patient received a total of eight injections of aflibercept. Further workup confirmed a suspected diagnosis of type 2 diabetes mellitus, and the patient was referred for primary care evaluation and management.
DISCUSSION These findings support the use of intravitreal aflibercept to reverse NVI and NVA as well as to control IOP in patients with NVG. Traditionally, PRP has been the gold standard treatment for NVG. Photocoagulation results in cellular destruction, reducing the hypoxic drive that results in upregulation of VEGF. By destroying ischemic tissue, VEGF production is mitigated, leading to regression of NVI and NVA.16,17 PRP does have adverse side effects, resulting in permanent visual field defects as well as reduced color vision and contrast sensitivity.8 Treatment with intravitreal anti-VEGF agents more directly addresses the pathophysiologic mechanism of ocular neovascularization by targeting the action of VEGF alone, thereby limiting and reversing the neovascular drive. Enthusiasm for treating NVG with anti-VEGF agents is tempered due to the necessity for repeated injections to maintain therapeutic outcomes. Patients in our study received ongoing injections at an initial interval of 4 weeks for the first three injections; subsequently, the interval was increased to 8 weeks. Patients were eligible for treatment with PRP or
© 2015 Royal Australian and New Zealand College of Ophthalmologists
806
SooHoo et al.
surgical intervention at the discretion of the treating physician. However, no patient required additional intervention during the 52-week study period. Intervals between injections were chosen based on established treatment protocols for neovascular AMD. It is possible, of course, that the optimal dosing interval for treatment of NVG is different. Further study is needed to investigate this possibility. The need for repeated anti-VEGF injections could be negated by the development of drug depots that can release medication at pre-specified intervals and doses. Possible approaches include poly(lactic-coglycolic)acid (PLGA) microspheres containing antiVEGF drug18 or a refillable mini drug pump.19 Longer term follow-up may also reveal that a ‘treat and extend’ approach, such as that used in the treatment of neovascular AMD,20,21 is a viable option in the management of NVG. Newer anti-VEGF agents or combination therapies that have more than one mechanism of action might also have a longer duration of action and allow for a longer interval between injections. Models of neovascular disease suggest that anti-VEGF therapy combined with an anti-platelet-derived growth factor agent more effectively reduces neovascularization compared to anti-VEGF treatment alone.22–24 Even if invasive filtration surgery is indicated to control IOP in NVG, pretreatment with an antiVEGF agent can reduce the risk of perioperative hyphema and improve IOP control in the postoperative period.25 Anti-VEGF treatment leads to more rapid regression of neovascularization than PRP and is therefore a more appropriate therapy prior to surgical treatment of NVG, especially if surgery is indicated urgently. Our findings show that intravitreal aflibercept may be a valid treatment option for NVG that is diagnosed prior to the development of synechial angle closure. Treatment with aflibercept can reverse NVI and NVA in early stages of NVG as well as stabilize or lower IOP. Limitations of this study include the small sample size and the fact that this was an open-label study without a matched group of control subjects. Our preliminary success suggests that aflibercept has the potential to delay or avoid the need for surgical treatment of NVG, if treatment is started early in the disease course. If surgery is indicated, treatment to induce regression of NVI and NVA may lower the risk of adverse events perioperatively and postoperatively. The optimal interval between treatments remains unclear and may need to be addressed on an individual or pro re nata basis. Further prospective studies are needed in larger cohorts of patients to better elucidate the clinical effects of aflibercept in NVG. Combination therapy with multiple agents, agents with multiple mechanisms of action and/or
extended release depots of anti-neovascular medications may further improve the utility and success of these treatments in the future.
ACKNOWLEDGEMENTS The authors would like to acknowledge the efforts of the University of Colorado retina service in performing the intravitreal injections and those of Naresh Mandava, MD (University of Colorado, Department of Ophthalmology) for acting as our internal medical monitor for this study.
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