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Treatment of proliferative diabetic retinopathy with anti-VEGF agents

2011; Wiley; Volume: 89; Issue: 5 Linguagem: Inglês

10.1111/j.1755-3768.2010.02079.x

1755-3768

Aysha Salam, Raeba Mathew, Sobha Sivaprasad,

Glaucoma and retinal disorders

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 & Miller 2009). The Diabetic Retinopathy Clinical Research Network (DRCRnet) (Research 2007–2010) is conducting a randomized controlled trial to determine whether intravitreal ranibizumab or a steroid given to patients with PDR and macular oedema can reduce the risk of visual loss following PRP and provide good visual outcomes over a short term. The primary outcome measure includes visual acuity outcomes at 14 weeks. Secondary outcome measures include changes in retinal thickness, presence and extent of new vessels on fundus photos and vitreous haemorrhage. Furthermore, proportion of patients in which additional sessions of PRP were required because of worsening of PDR before 14 weeks will also be analysed. Bevacizumab (Avastin; 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 & Fawzi 2009). Bevacizumab is not currently licensed for intraocular use, but it remains the most popular among all anti-VEGF agents. To date, there are three published randomized nonplacebo control trials on the use of intravitreal bevacizumab for the treatment of PDR (Mirshahi et al. 2008), (Tonello et al. 2008), (Rizzo et al. 2008). Several clinical trials are currently underway (clinicaltrials.org). The two main indications that are being explored include patients with active PDR requiring PPV and patients with neovascular glaucoma. Bevacizumab has been shown to reduce intra- and postoperative bleeding and surgical operating times when used as a pre-operative adjunct during the surgical removal of vitreomacular membranes (Chen & Park 2006), (Yeoh et al. 2008), (Krzystolik et al. 2006), (Rizzo et al. 2008), (Ishikawa et al. 2009), (Yang et al. 2008). It is also useful as a pre-operative adjunct for reducing vitreous haemorrhage before laser treatment can be initiated (Mirshahi et al. 2008), (Spaide & Fisher 2006),(Arevalo & Garcia-Amaris 2009), (El-Batarny 2007). The optimal dose and dosing sequence for bevacizumab remains unclear. Most studies have used a dose of 1.25 mg (Mirshahi et al. 2008), (Spaide & Fisher 2006), (Isaacs & Barry 2006), (Chen & Park 2006), (Friedlander & Welch 2006), (Arevalo et al. 2009), (Rizzo et al. 2008), (Ishikawa et al. 2009), (Torres-Soriano et al. 2009), (Yang et al. 2008), (Arevalo et al. 2008), (Tranos et al. 2008), (Lee & Koh 2008), (El-Batarny 2007). Arevalo et al. (2009) used dosages of 1.25 mg (20.5%) and 2.5 mg (79.5%), depending on the discretion of the treating clinician, and noted that the 2.5-mg dosage was more effective in inducing complete regression of neovascularization relative to the 1.25-mg dose in treatment of naïve eyes. In contrast, Avery et al. (2006) reported no significant differences between the effect of various doses of bevacizumab, ranging from 6.2 μg to 1.25 mg, on retinal neovascularization. However, they hypothesized that durability of the drug effect may vary, with higher doses producing a longer duration of effect. Likewise, the frequency of bevacizumab for these indications remains unclear. Most studies deferred re-injections to cases that only showed recurrence (Arevalo et al. 2009). Notably, caution should be exercised with high doses of bevacizumab (2.5 mg) in patients with a compromised foveal avascular zone (FAZ) (Lee & Koh 2009). All anti-VEGF agents have shown promising results with regard to the regression of neovascularization, but they were limited by their short duration. None of the agents can substitute for the remarkable durability of PRP that qualifies it as the gold standard treatment for PDR. The average time to recurrence of retinal neovascularization following anti-VEGF treatment ranged from 2 weeks (Avery et al. 2006) to 3 months (Spaide & Fisher 2006), (Avery 2006), (Thew 2009). An accurate comparison of the efficacy and potency of these agents is difficult. Persistence of the effect of treatment 6 months postinjection appears to be a standard average endpoint for evaluating the effectiveness of anti-VEGF treatments. Unfortunately, very few of the studies included a 6-month follow-up. A comparative analysis between studies is difficult because quantitative measures of the extent and severity of neovascularization differ between individuals. The effect of anti-VEGF agents on high-risk PDR should lead to an increased understanding of the effect of these agents in clinical practice. Over a 28-week period following bevacizumab treatment, Arevalo reported that 61.4% of patients showed complete regression without fluorescein leakage, 34% of patients showed a partial regression and 4.5% of patients showed no regression of neovascularization (Arevalo et al. 2009). Mendrinos et al. (2009) reported the complete regression of neovascularization 1 year after a single injection of pegaptanib in a patient with previous PRP. In a retrospective analysis of 16 patients with PDR, Adamis et al. (2006) reported a possible persistent beneficial effect with intravitreal pegaptanib, with 62% of the treated eyes (n = 13) showing regression or a lack of neovascularization at the 6-month follow-up visit; 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 & Fisher 2006). In this way, anti-VEGF agents would reduce the time required for vitreous clear-up and decrease the need for PPV by approximately 30% (Jonas et al. 2008), (Huang et al. 2009). Anti-VEGF agents have shown a promising role in the management of neovascular glaucoma (NVG), which represents one of the most severe forms of secondary glaucoma. Costagliola et al. (2008) conducted a prospective pilot trial on 26 eyes with NVG. At the end of the treatment schedule, which included three intravitreal bevacizumab injections 1 month apart, regression of neovascularization was noted in all patients with intraocular pressure (IOP) reductions ranging from 30–0 mmHg (mean: 13 mmHg). However, at the annual follow-up, three eyes required glaucoma valve implants and 14 patients needed glaucoma medication. Lim et al. (2009) showed remarkable regression of iris neovascularization over a 2-week period with a significant reduction in intravitreal VEGF levels and no significant changes in IOP or corneal endothelial cells in NVG patients treated with intracameral injection of bevacizumab. Likewise, Chalam et al. (2008) reported complete regression of neovascularization within 3 weeks postinjection, reducing the need for surgery in patients with aggressive NVG treated with intracameral injection of bevacizumab. Eid et al. (2009) recently carried out a comparative study of 20 patients with intractable glaucoma, all of whom underwent shunt procedures. Ten patients were given bevacizumab 1–2 weeks prior to surgery, followed by PRP; 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 blockage of the trabecular meshwork by bevacizumab, which is a large 148-kDa protein, with the internal limiting membrane acting as an additional barrier (Jalil et al. 2007a,b). Other serious ocular side-effects reported include endophthalmitis (0.16%) (36), retinal pigment epithelial tear (0.14%), lens injury (0.14%) and acute visual loss (0.14%) (Shima et al. 2008). Macular hole has been reported after bevacizumab in PPV in diabetic eyes (Gandhi et al. 2009), (Mitamura et al. 2008), which is believed to be because of bevacizumab-related rapid neovascular involution with accelerated fibrosis, posterior hyaloid contraction and macular hole retinal detachment. However, the causative role of pre-existing PDR cannot be excluded. Lee & Koh (2009) reported one case of an angiographically documented FAZ enlargement following PPV and treatment with 2.5 mg of bevacizumab, attributing it to a nonselective blockage of both pathological and physiological levels of VEGF thought to be essential for maintaining foveal circulation and visual acuity. The mechanism of action has been linked to endothelial dysfunction associated with a lack of nitric oxide production, which in turn leads to vessel wall constriction, leucocyte adherence causing blockage of capillaries and capillary drop-out. This is further complicated by pre-existing microvascular angiopathy, which is seen as a common denominator in diabetic patients that adds insult to injury. In contrast, Neubauer et al. (2007) assessed macular ischemia angiographically in 19 patients with CSMO postbevacizumab and showed an improvement in peripheral ischemia. Avery et al. (2006) reported a subtle decrease in the leakage of retina or iris neovascularization in the uninjected eye of two patients, raising the possibility that systemic therapeutic levels were achieved after intravitreal injection. In contrast, Sawada et al. (2008) reported either a minimal effect or no effect following intravitreal injection of bevacizumab in the uninjected eye. Further studies are needed to ascertain the systemic side-effects of anti-VEGF agents and the safety implications that might be related to them, especially in diabetic subjects with significant comorbidities. Systemic hypertension has been reported to be the most common side-effect (5.6%), followed by other cardiovascular complications (Rosenfeld et al. 2006), (Gragoudas et al. 2004), (Roth et al. 2009). Lastly, Kumar et al. (2010) provided a word of caution, especially for women of child bearing age; as the average age of patients with PDR is significantly younger than with the average age of patients with ARMD, there is a potential risk of teratogenicity, carcinogenicity and impairment of fertility with the use of anti-VEGF agents. Counselling of patients is therefore essential to ensure that adequate contraception is being used and that possible systemic side-effects are understood. Panretinal photocoagulation remains the gold standard of care for all patients with PDR. At present, the only indications for anti-VEGF agents in PDR include its use as a safety net in patients with intragel haemorrhage awaiting photocoagulation, to expedite the nonclearing haemorrhage, pre-operatively prior to vitrectomy for vitreous haemorrhage and delamination and pre-operatively in neovascular glaucoma to reduce the rubeosis and facilitate antiglaucoma interventions. Although extremely efficient in causing the regression of neovascularization as early as 24 hr postinjection (Avery et al. 2006), reperfusion of abnormal vessels will always be a limiting factor for anti-VEGF treatment. Finally, caution should be exercised in cases of PDR with pre-existing pre-retinal fibrosis, as anti-VEGF agents can cause TRD. Table 1: Summary of the published studies on antiVEGF agents in proliferative diabetic retinopathy and associated complications. As a service to our authors and readers, this journal provides supporting information supplied by the authors. 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