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 eyes^7,8 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

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