Treatment of proliferative diabetic retinopathy with anti-VEGF agents

Proliferative diabetic retinopathy (PDR) is the most common cause of severe visual loss in people with diabetes. Although panretinal photocoagulation (PRP) remains the gold standard of care to date, several combinations of new treatment modalities have emerged. These approaches can be used to increase the extent of treatment, expedite the effect of laser treatment and provide alternate measures when laser delivery is difficult or impossible, especially in patients with vitreous haemorrhage. Currently, most of the research in this field is focussed on inhibitors of vascular endothelial growth factor (VEGF), referred to herein as anti-VEGF agents. Although limited by their short-lived effects and a lack of established protocols, anti-VEGF agents are widely available, especially for the treatment of aggressive PDR. This review analyses published studies using anti-VEGF agents alone or as an adjunct to other therapies in the treatment of PDR. Proliferative diabetic retinopathy (PDR) is a leading cause of blindness (Kempen et al. 2004). Currently, the only evidence-based treatment for PDR is panretinal photocoagulation (PRP), which reduces the risk of severe visual loss by 50–60% with regression of the majority of neovascularizations over a period of 3 months (Group 1981). The proposed mechanisms underlying PRP include reduced oxygen demands associated with destruction of the highly metabolically active outer retinal cells and improved retinal oxygenation from the choroidal circulation. Several investigators have attempted to modify PRP laser techniques to decrease laser-related side-effects, including decreased visual acuity, peripheral field loss and macular oedema (Brucker et al. 2009). Nonetheless, many patients require periodic supplemental laser treatment, and nearly 4.5% show disease progression that ultimately requires pars plana vitrectomy (PPV), even when PRP was considered ‘adequate’ (Flynn et al. 1992). Alternate treatment options have been attempted in an effort to provide better outcomes and/or reduced side-effects. With the advent of anti-vascular endothelial growth factor (VEGF) agents (Adamis et al. 1994), studies have focussed on their role in the management of PDR. This review summarizes the available literature on this subject. Comprehensive searches for published studies that evaluated the effects of anti-VEGF agents on PDR from January 2003 to August 2010 were performed using three electronic bibliographic databases: MEDLINE, EMBASE and CINAHL; clinical trial databases (clinicaltrials.gov) were also searched. Furthermore, abstracts from the Association for Research in Vision and Ophthalmology (2003–2010), reference lists from identified studies and key review articles assessing the effects of anti-VEGF agents for PDR treatment were searched. While no language restrictions were applied, in practice, the search was restricted to English-language papers and those with English-language abstracts. The search strategy included the following search terms: PDR, retinal neovascularization, vitreous haemorrhage and rubeosis iridis combined with anti-VEGF, bevacizumab or Avastin Macugen or pegaptanib, Lucentis or ranibizumab. Information on study design, outcomes and analysis was documented on a standardized data extraction form (Summary; Table S1). Information entered into the database included: Study design; Method of randomization and masking in randomized controlled trials (RCTs); Diagnostic criteria (biomicroscopy/leakage on fundus fluorescein angiography FFA); Drug dose and treatment regimen; Incidence of reperfusion of neovascularization after treatment and persistence of effect of treatment at last follow-up; Time to laser treatment or PPV; and Adverse events. Two investigators (AS and RM) independently identified and grouped the studies before these data were entered and analysed. All differences were resolved by discussion with the senior investigator (SS). Articles considered irrelevant to PDR and duplicate studies were excluded. Primary outcome measures compiled from these studies included the time to regression of new vessels and the time to recurrence of new vessels. The proportion of patients whose treatment effect (defined as the absence/regression of new vessels) lasted for at least 6 months after one injection was also recorded. Secondary outcome measures compiled from these studies included the effect of treatment on the best-corrected visual acuity (BCVA), effect of treatment in patients with nonclearing vitreous haemorrhage and local and systemic side-effects. In addition, a decision was made in advance to extract all other clinically relevant data reported by the investigators. Pegaptanib sodium (Macugen, Eyetech Inc, Cedar Knolls, NJ, USA) is a 28-nucleotide RNA aptamer that binds specifically to the VEGF-A165 isomer, which is the major pathological VEGF protein in the eye (Ng et al. 2006). Aptamers are nonimmunogenic and are less likely to cause tolerability issues (Lee et al. 2006). A phase II, prospective randomized clinical trial evaluated the effects of intravitreal pegaptanib treatment on diabetic macular oedema (Adamis et al. 2006). A retrospective analysis was also carried out to compare the effect of intravitreal pegaptanib on ocular neovascularization relative to a sham group in the same study. Of the 172 participants in the study, only 16 subjects were included in the retrospective analysis. With regard to ocular neovascularization, eight subjects (62%) in the intravitreal pegaptanib group (n = 13) showed regression of neovascularization at 36 weeks, whereas none of the eyes from sham group (n = 3) showed regression of ocular neovascularization. However, in three of the eight treated eyes (37.5%), ocular neovascularization was observed to recur at week 52 after cessation of pegaptanib at 30 weeks. Ranibizumab (Lucentis®; Genentech USA, Inc., San Francisco, CA, USA/ Novartis ophthalmics, Basel, Switzerland) is an engineered recombinant humanized antibody fragment (Fab) that is active against all VEGF-A isoforms. As it is a small antibody fragment that lacks the Fc domain, it has a much shorter half-life than other anti-VEGF agents (Hussain et al. 2007). It is currently licensed as an intravitreal agent for wet age-related macular degeneration (ARMD). There are no published reports on the effect of ranibizumab on PDR (Jardeleza Genentech Inc., San Francisco, CA, USA) is a full-length recombinant humanized antibody active against all isoforms of VEGF-A. This large sized molecule (molecular weight: 148 kDa) offers an advantage in that its half-life is twice that of ranibizumab, which is presumed to be associated with a prolonged effect on retinal neovascularization (Abdallah however, the mean number of injections was five (range: 3–6), and only one patient had high-risk PDR. A 3-month re-injection or follow-up rate would appear to be reasonable timing in most cases, especially for managing patients with high-risk PDR. Minnella reported that the early effects of bevacizumab were maintained at 3 months in 15 injected eyes (Minnella et al. 2008). Likewise, Schmidinger et al. (2009) reported that 62% (8 of 13) eyes required re-treatment with bevacizumab at a 3-month follow-up visit because of the reappearance of new vessels. PRP in patients with PDR mandates clear media and a better fundoscopic view to allow photocoagulation of the ischaemic retina. Extensive vitreous haemorrhage precludes the possibility of laser photocoagulation. The most common strategy currently used for dealing with these patients is close observation until the blood has reabsorbed to provide a sufficient view or surgical intervention to remove the blood and fibrovascular tissue with PRP at the time of surgery. However, administration of anti-VEGF agents has shown promising results in nonclearing dense vitreous haemorrhage by a largely unknown mechanism. It is thought that injection of anti-VEGF agents would stop the further leak of blood into the vitreous cavity by causing regression of the neovascularization while the concomitant resorption of haemorrhage would remain unresolved (Spaide 10 eyes were used as historical controls with PRP performed pre-operatively and none postoperatively. The mean IOP drops were 18.8 and 15.9 mmHg with success rates of 85% and 70% in the bevacizumab and control groups, respectively, over a 1-year follow-up. The authors concluded that combining bevacizumab with good PRP ablated the ischaemic retina and ensured good success rates; the effects of bevacizumab are temporary, and the PRP provides a more permanent reduction in angiogenic ischaemic stimuli. It can also be assumed that success of surgery would be better in less inflamed eyes with reduced intra-operative bleeding. Importantly, in the current climate of increasing tendency to use anti-VEGF agents, it would be invaluable to know the best timing of injection pre-operatively and the measures that should be taken in advance to pre-empt surgery. It has been postulated that if bevacizumab is administered when the anterior chamber angle is still open, prior to the formation of peripheral anterior synechiae (PAS) and angle closure, further surgical intervention is more likely to be avoided than when it is administered at a later stage. Despite the useful effects on ocular neovascularization, bevacizumab can cause tractional retinal detachment (TRD) in patients with severe PDR (Torres-Soriano et al. 2009). It is hypothesized that bevacizumab accelerates the occlusion of new vessels by replacing them with fibrous tissue. The contraction of this fibrous tissue can cause TRD and vitreous haemorrhage (Kuiper et al. 2008), (Yeh et al. 2009), (Jonas et al. 2009). Other proposed mechanisms include extreme fluctuations in IOP (Arevalo et al. 2008) and mechanical deformation of the globe during intravitreal injection with possible vitreous incarceration in the scleral wound, resulting in vitreoretinal traction (Tranos et al. 2008). Torres-Soriano et al. (2009) reported a TRD rate of 1.45% over a period of 1–6 weeks after intravitreal injection; however, TRD in this case may be attributed to intravitreal injection or the natural history of disease. The time interval between bevacizumab treatment and TRD could suggest a risk imposed by bevacizumab, further strengthened by the fact that 82% of TRD developed within 5 days of injection (Arevalo et al. 2008). To date, Moradian et al. (2008) have reported the longest interval between bevacizumab and TRD of 2 months in two patients with severe PDR. The highest incidence of progression of pre-existing TRD has been reported as 18% over a 2- to 30-day period (Oshima et al. 2009). Krishan reported an interval of 3–5 weeks following intravitreal pegaptanib treatment, which is the only reported case of TRD after pegaptanib to date (Krishnan et al. 2009). Suggested risk factors for TRD following bevacizumab include a longer time interval between bevacizumab and PPV in patients with poorly controlled diabetes and PDR resistant to PRP (Ahmadieh et al. 2009), (Yeh et al. 2009). Yeh et al. (2009) recommend a week or less between bevacizumab and PPV, as they reported a higher incidence of subretinal bleeding, possibly related to increased traction and microbreak formation. Other side-effects of bevacizumab include retinal haemorrhages, presumably caused by inhibition of all VEGF-A isoforms (Lee & Koh 2008). Uveitis is also a reported side-effect, particularly at higher doses, with an incidence of 0.09–1.9% (Wu et al. 2008), (Ladas et al. 2009). Transient IOP rise is also another recognized complication with a frequency of 0.16% with bevacizumab (Wu et al. 2008). Frenkel et al. (2007) recorded transient IOP spikes within 1 min, 20 min and 30 min of treatment and showed a significant rise in IOP that diminished within the next 30–60 min. They show no difference between the pre-operative IOP and the IOP at next clinic visit, although the time interval was not described. A possible explanation could include a temporary rise in the vitreous volume leading to an increase in IOP. A case report by Jalil et al. described the longest duration of IOP elevation, with an IOP spike of 56 mmHg at 3 days after the fourth injection that normalized with a maximal dose of antiglaucoma medication at 11 weeks postinjection in a patient with ocular hypertension (Jalil et al. 2007a,b). The most likely explanation for the raised IOP includes of the by bevacizumab, which is a large with the as an additional (Jalil et al. 2007a,b). Other ocular side-effects reported include retinal and visual loss et al. 2008). has been reported after bevacizumab in PPV in diabetic eyes et al. 2009), et al. 2008), which is to be because of neovascular with contraction and macular retinal However, the role of pre-existing PDR be excluded. & Koh (2009) reported one case of an documented following PPV and treatment with 2.5 mg of bevacizumab, it to a of pathological and levels of VEGF thought to be for foveal and visual The of has been to endothelial associated with a lack of which in to causing of and This is further by pre-existing which is as a common in diabetic patients that to In contrast, et al. (2007) macular in patients with and showed an in peripheral Avery et al. (2006) reported a decrease in the of retina or iris neovascularization in the eye of two the possibility that systemic levels were after intravitreal In contrast, et al. (2008) reported a effect or no effect following intravitreal injection of bevacizumab in the studies are needed to the systemic side-effects of anti-VEGF agents and the that be related to especially in diabetic subjects with significant hypertension has been reported to be the most common followed by other et al. 2006), et al. et al. 2009). et al. a of especially for of as the average of patients with PDR is than with the average of patients with there is a risk of and of with the use of anti-VEGF agents. of patients is to that is being used and that possible systemic side-effects are photocoagulation remains the gold standard of care for all patients with PDR. At the only indications for anti-VEGF agents in PDR include its use as a in patients with haemorrhage to expedite the nonclearing pre-operatively prior to vitrectomy for vitreous haemorrhage and and pre-operatively in neovascular glaucoma to reduce the rubeosis and antiglaucoma Although in causing the regression of neovascularization as early as postinjection (Avery et al. 2006), reperfusion of vessels will be a factor for anti-VEGF caution should be exercised in cases of PDR with pre-existing as anti-VEGF agents can cause Table of the published studies on agents in diabetic retinopathy and associated As a to authors and this provides by the are and may be for but are not issues from than should be to the The is not for the or of by the than should be to the for the