Anti-VEGF Therapy in Vitrectomized Eyes
Michael Waisbourd, MD • Anat Loewenstein, MD
The results of the MARINA,1 ANCHOR,2 DRCR.net,3 CRUISE4 and BRAVO5 studies provide mounting evidence of the efficacy of anti-VEGF drugs in various retinal pathologies, and intravitreal injections are being performed in increasing numbers.
Some of the injected patients have undergone a previous vitrectomy surgery for various reasons. Among these patients are individuals with proliferative diabetic retinopathy who had nonclearing vitreous hemorrhages for which they underwent pars plana vitrectomy (PPV) and now present with diabetic macular edema, necessitating anti-VEGF treatment. Most of the large, randomized, controlled studies of anti-VEGF drugs were performed in eyes with na�ve vitreous. The effect of the injected drug may, however, be altered in eyes that had previously been vitrectomized, and it is not clear how those eyes will react to anti-VEGF therapy.
It is well known that cataract surgery in vitrectomized eyes carries higher risks and complications than nonvitrectomized eyes. Surgical challenges include a deep, fluctuating anterior chamber, an excessively mobile posterior capsule, and weakened zonules. There is also loss of vitreous support and increased risk for retinal detachment.6
Moreover, the incidence of an iatrogenic retinal break occurring during an intravitreal injection in previously vitrectomized eyes has not been investigated in depth. Other possible untoward consequences are further damage to the lens zonules or iatrogenic traumatic cataract formation during injection of an eye that does not contain a stabilizing vitreous scaffold.
Sustained, elevated intraocular pressure postinjection is a recent finding that was reported in nonvitrectomized eyes7,8 and might also be evident or altered in these eyes, as could be postinjection endophthalmitis and uveitis.
Another area in question is whether replacement of vitreous alters VEGF and anti-VEGF pharmacokinetics. Replacement of the vitreous gel with less viscous saline or aqueous humor facilitates oxygen transport to ischemic retinal areas, as well as clearance of VEGF from these areas, thus reducing edema and retinal neovascularization.9 The enhanced clearance of VEGF postvitrectomy was demonstrated by Lee et al.10 They performed VEGF165 injections in rabbit eyes with and without PPV and measured vitreous VEGF levels as a function of time. They found a more rapid decrease of mean vitreous VEGF levels in eyes that had been subjected to PPV than in non-PPV eyes. The vitreous VEGF half-life in PPV eyes was 10 times shorter than that in normal eyes.
A recent study presented at ARVO showed that the half-life of intravitreally injected bevacizumab in vitrectomized macaque eyes was reduced by 60% compared with nonvitrectomized eyes. Moreover, the effect of intravitreally injected bevacizumab on the concentration of aqueous VEGF lasted for a much shorter period of time in the vitrectomized eyes compared with nonvitrectomized eyes.11
Several clinical studies in humans investigated the efficacy of anti-VEGF drugs and yielded opposite conclusions in different retinal pathologies. Metha et al. retrospectively evaluated records of 60 eyes that underwent intravitreal bevacizumab therapy for refractory DME. They found that vitrectomized eyes had worse visual acuity and central retinal thickness outcomes (P = .002 and P = .028, respectively) compared with nonvitrectomized eyes.12
Another study retrospectively reviewed 11 eyes of 10 patients who underwent intravitreal bevacizumab injections for persistent DME after a PPV that failed to resolve the edema. Those patients received monthly bevacizumab injections for three months and failed to demonstrate any change in either foveal thickness or visual acuity.13
A different study undertaken by Connor did find ranibizumab to be beneficial in vitrectomized eyes. In this small, retrospective, noncomparative study, the investigator reviewed the files of 10 patients who had undergone a PPV for different retinal pathologies and were subsequently diagnosed with neovascular AMD after a mean of 5.8 years. Their mean visual acuity improved from 20/182 to 20/74 after a mean of 5.6 injections of ranibizumab, and their gain in Snellen lines ranged from one to five lines, with a mean of three lines.14
Yet another consideration concerns the use of anti-VEGF agents in vitrectomized eyes as part of combination therapy. In such eyes, agents that are intravitreally injected clear more quickly, affecting the efficacy of the drugs. With the approval of Allergan's Ozurdex dexamethasone implant and its tested efficacy in treating DME in previously vitrectomized eyes, it has been suggested that Ozurdex may augment treatment with anti-VEGF agents.15
Questions arise as to how these conflicting results should be interpreted and whether there really is a difference between the efficacy of bevacizumab and ranibizumab after PPV. Also, it remains unclear whether an increased clearance of anti-VEGF drugs requires shorter treatment intervals. Finally, it needs to be established whether or not vitrectomized eyes have greater systemic absorption. Welldesigned studies are clearly warranted in order to address these interesting issues. RP
1. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular agerelated macular degeneration. N Engl J Med. 2006;355:1419-1431.
2. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1432-1444.
3. Elman MJ, Bressler NM, Qin H, et al. Expanded 2-year Follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011;118:609-14.
4. Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117:1124-33 e1.
5. Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117:1102-12 e1.
6. Shousha MA, Yoo SH. Cataract surgery after pars plana vitrectomy. Curr Opin Ophthalmol. 2010;21:45-49.
7. Good TJ, Kimura AE, Mandava N, Kahook MY. Sustained elevation of intraocular pressure after intravitreal injections of anti-VEGF agents. Br J Ophthalmol. 2011;95:1111-1114.
8. Tseng JJ, Vance SK, Della Torre KE, et al. Sustained increased intraocular pressure related to intravitreal antivascular endothelial growth factor therapy for neovascular age-related macular degeneration. J Glaucoma. 2011 Mar 16. [Epub ahead of print]
9. Stefánsson E. Physiology of vitreous surgery. Graefes Arch Clin Exp Ophthalmol. 2008;247:147-163.
10. Lee SS, Ghosn C, Yu Z, et al. Vitreous VEGF clearance is increased after vitrectomy. Invest Ophthalmol Vis Sci. 2009;51:2135-2138.
11. Kakinoki M, Miyake T, Sawada O, Sawada T, Kawamura H, Ohji M. The clearance of intravitreal bevacizumab in vitrectomized macaque eyes. Poster presented at: Annual meeting of the Association for Research in Vision and Ophthalmology; Fort Lauderdale, FL; May 5, 2011.
12. Mehta S, Blinder KJ, Shah GK, Kymes SM, Schlief SL, Grand MG. Intravitreal bevacizumab for the treatment of refractory diabetic macular edema. Ophthalmic Surg Lasers Imaging. 2010;41:323-329.
13. Yanyali A, Aytug B, Horozoglu F, Nohutcu AF. Bevacizumab (Avastin) for diabetic macular edema in previously vitrectomized eyes. Am J Ophthalmol. 2007;144:124-126.
14. Helzner J. Lucentis in vitrectomized eyes. Retinal Physician. 2010;7(7):8.
15. Helzner J. Sustained-release drugs: heralds of the future. Ophthalmol Mgmt. 2010;14(3):41-43,45-46,48.
|Michael Waisbourd, MD, is on the faculty of the department of ophthalmology at the Tel-Aviv Sourasky Medical Center in Israel and is on the Sackler Faculty of Medicine at Tel-Aviv University. Anat Loewenstein, MD, is the head of the department of ophthalmology at the Tel-Aviv Sourasky Medical Center and vice dean of the Sackler Faculty of Medicine at Tel-Aviv University. Dr. Waisbourd reports no financial interest in the products or companies discussed in this article. Dr. Loewenstein reports moderate financial interest in Notal Vision, Israel. Dr. Waisbourd can be reached via e-mail at email@example.com.|