Risk Factors Of Pdr Progression

Published Date: 02 Nov 2017

Abstract

Proliferative diabetic retinopathy (PDR) is an advanced form of diabetic retinopathy. It is characterised by neovascularisation in the retina or optic disc, which occurs as a result of retinal ischemia. PDR is a major cause of blindness and visual impairment in diabetic patients worldwide. Early detection and timely intervention with the appropriate treatment is necessary in order to prevent and reduce the risk of visual loss in patients with PDR. Pan retinal Photocoagulation (PRP) remains the cornerstone and first line of care to date, however, it can cause significant side effects and irreversible retinal damage. A number of different treatment modalities have emerged which have been used in combination with PRP to reduce the damage. Moreover, recently much research has focussed on anti-vascular endothelial growth factors known as anti-VEGFs for the treatment of PDR. The aim of this dissertation was to analyse published studies that have used VEGF agents alone or as an adjunct to other therapies to treat this disease and compare it to PRP to determine the best form of treatment for the management of PDR. This study found that although anti-VEGFs have shown promise, not enough studies have used these agents for the treatment of this disease. Furthermore like PRP, anti-VEGFs have shown to cause side effects. Whilst both PRP and anti-VEGFS have their advantages and limitations, it is clear both forms of treatments have a significant role to play in the treatment and management of PDR. Further studies are needed to test the safety and efficacy of anti-VEGFs. The future of these drugs looks promising for the treatment and management of PDR.

Introduction

1.1 Proliferative diabetic retinopathy

Proliferative diabetic retinopathy (PDR) is an advanced form of diabetic retinopathy that occurs as a result of retinal ischemia. It is characterized by the growth of abnormal blood vessels, termed as neovascularisation, which extend over the surface of the retina. Neovascularisation may occur on or within one disc area of the optic disc, referred to as neovascularisation of the disc (NVD). Alternatively, new vessel growth may occur on the retina in locations greater than one disc area of the optic nerve head, and is known as neovascularisation elsewhere (NVE) (figure 1: a&b Chris Steele et al., 2003). 131

B

A

NVE

NVD

Figure 1: A) Optic disc neovascularisation (NVD) and B) neovascularisation elsewhere (NVEs) (Chris Steele et al., 2003)

Neovascularisation can lead to bleeding within the retina which results in pre-retinal and vitreous haemorrhages. Furthermore, Fibrous tissue accompanies the development of the new vessels and can lead to tractional retinal detachment. These primary complications represent a severe form of PDR that often result in permanent vision loss. Secondary complications include neovascularisation of the iris leading to neovascular glaucoma.

PDR may be characterised as either being high-risk or non-high-risk PDR for vision loss. A patient exhibiting three or four of the following features is considered as having high-risk proliferative retinopathy and is at risk of serious vision loss. These features include: new vessels on or within one disc diameter of the optic disc, presence of neovascularisation elsewhere on the retina, presence of vitreous or pre-retinal haemorrhage, and moderate to severe extent of neovascularisation. Conversely, non -high risk PDR has one or two of the above features and therefore does not meet the criteria for high-risk PDR.

Clinically, symptoms associated with PDR include blurred vision, floaters, loss of central or peripheral vision, and flashes of light. (SOFOLAHAN THESIS)

1.2 Risk factors of PDR progression

A number of risk factors are associated with the development of PDR and its progression. The presence of diabetes at an early age and the duration of diabetes are linked with a higher risk of retinopathy development and its progression to PDR. The level of glycaemic control is another important factor in determining the extent and progression of PDR. An intensive control of glycaemia reduces the risk of retinopathy by 40% and its progression to sight-threatening PDR by 25%. Furthermore, the need for laser therapy and risk of blindness due to PDR is reduced by 25% and 15% respectively (check Lancet review). The control systemic hypertension has shown to reduce the risk of diabetic retinopathy (DR) and it progression to PDR, and therefore its presence is associated with a high risk of developing DR and PDR. Pregnancy has also been implemented as a risk factor for the progression of retinopathy. Other risk factors associated with PDR progression include smoking, obesity and hyperlipidaemia.

Vitreous haemorrhage and tractional detachment as well as being complications of PDR, also exaggerates PDR progression and are important risk factors in causing visual loss. The development and progression of diabetic retinopathy is also controlled by various cytokines to some degree. The balance between the vascular endothelial growth factor (VEGF), which is an angiogenic stimulator, and the angiogenic inhibitor, pigment epithelium-derived factor (PEDF) is a significant factor in the development of abnormal retinal vessels (Agnieszka Kobierzycka-Bala 2007).

1.3 Prevalence of PDR

Proliferative diabetic retinopathy is a major cause of blindness throughout the world. It has been estimated that approximately 17 million people suffer from PDR globally. On the basis of the data collated from 35 studies worldwide, on more than 20,000 participants with diabetes, Joanne et al 2012 estimated that among individuals with diabetes, the overall prevalence of PDR was 7.0%.

In the United Kingdom1, 37,000 new cases of PDR are reported annually. Between five to ten per cent of all diabetics develop proliferative diabetic retinopathy. PDR is more common in patients with type 1 diabetes (40%) than type 2 diabetes (20%). It is estimated that 60% of type 1 diabetic patients after having had diabetes for a duration of 30 years show signs of PDR.

2.0 Aims and objectives of this study

These figures highlight the substantial public health burden of this disease. The prevalence of PDR is expected to rise with the increase in type II diabetes in the next few years. Therefore, early detection and timely intervention with adequate treatment is necessary to avoid further visual loss and complications. Laser Pan retinal photocoagulation (PRP) is still the first-line treatment of choice for patients with high risk PDR. Recently, other forms of treatments such as anti-VEGFs have been investigated for the treatment of PDR.

This dissertation explores published studies that have used VEGF agents alone or as an adjunct to other therapies to treat this disease and compares it to PRP to determine the best form of treatment for the management of PDR. A thorough review of the current literature is performed and each study is critically analysed, thereby giving us a better understanding of the effectiveness of each treatment.

3.0 Treatments

3.1 Pan retinal photocoagulation

Pan retinal photocoagulation (PRP) is the primary form of treatment for PDR (Cheung et al., 2010). The goal of the treatment is to cause regression of the proliferating new vessels and prevent the onset of newly formed ones (Porta and Bandello, 2002). A series of laser burns are induced over the peripheral fundus, covering the entire retina but sparing the central macula (Aiello et al., 1994; Cheung et al., 2010). It has been proposed that PRP indirectly promotes regression of retinal neovascularization by reducing ischemia and VEGF production (Cheung et al., 2010; ETDRS 1991; Glaser et al., 1987).

The efficacy of pan retinal photocoagulation for the treatment of PDR was firmly established from two major clinical trials in ophthalmology, the Diabetic Retinopathy Study (1981) and the Early Treatment Diabetic Retinopathy Study (1991), respectively.

The aim of the DRS study was to determine whether photocoagulation helped prevent severe visual loss in patients suffering from proliferative diabetic retinopathy. It was a randomised controlled clinical trial involving more than 1700 patients with proliferative disease. Patients participated in the study if they were under the age of 70, had PDR in at least one eye or severe NPDR in both eyes, and had VA of 20/100 or better in each eye. Participants were randomly assigned to receive PRP in one eye whilst the other eye was used as a control and received no treatment. Severe vision loss was defined as VA < 5/200 on two consecutive follow-up exams, 4 months apart. The results of the study demonstrated that pan retinal photocoagulation (PRP) reduced the risk of severe vision loss by at least 50% in patients with high-risk PDR compared to a control group over a period of 5 years. The study also showed that patients who had high risk characteristics such as the presence of vitreous haemorrhage or pre-retinal haemorrhage also benefited from PRP treatment. However, PRP seemed to have no substantial benefit in eyes with PDR without high-risk characteristics (DRS 1981).

In the ETDRS study, a total of 3711 patients were recruited and evaluated for a period of four years. The patients had less severe diabetic retinopathy compared to those enrolled in the DRS study. Patients were eligible if there were aged between 18 and 70 years and had moderate or severe non-proliferative diabetic retinopathy or mild proliferative retinopathy in both eyes, with no previous history of photocoagulation treatment. Furthermore, the patients were required to have a visual acuity of 20/40 or better. The results of the study demonstrated that early use of this therapy reduces risk of progression to high-risk proliferative retinopathy by half in eyes with very severe NPDR and macular oedema (ETDRS 1991). Whilst the DRS and ETDRS studies showed promising results for severe PDR, the study also suggested that less severe stages of diabetic retinopathy may not benefit from laser treatment (DRS 1981; ETDRS 1991; Cheung et al., 2010).

Other smaller scale studies have also investigated the role of PRP in the treatment of PDR (Doft and Blankenship, 1984; Vander et al., 1991). Doft and Blankenship 1984 demonstrated that neovascularisation of vessels regressed rapidly after laser photocoagulation treatment. They found the incidence of eyes that had a high risk for severe visual loss decreased significantly three weeks after treatment (Doft and Blankenship, 1984). In another study, Vander et al 1991 noted that 50-60% of patients had regression of the majority of neovascularisation within 3 months of treatment. The visual prognosis was shown to be excellent when PDR regressed within the first 3 months following PRP treatment. Approximately half (52%) of the patients had a final visual acuity of 20/20 after the four years follow up period. Therefore, the study concluded that PRP was beneficial in treating PDR and the long term visual prognosis after PRP use seemed to be excellent (Vander et al., 1991).

3.2 Pan Retinal Photocoagulation side effects and limitations

Although PRP has shown efficacy in preventing severe vision loss, unfortunately its use is often associated with significant risks and ocular side effects. Ocular side effects include loss of peripheral vision, small decrease in visual acuity, difficulty with light and dark adaptation and worsening of macular oedema. Further side effects associated with this treatment are pain and night blindness (Cheung et al., 2010; Mohamed et al., 2007). Moreover, there is risk of causing blindness with accidental burns to the fovea if the eye moves during therapy. PRP is not without its limitations either, as it is difficult to treat patients suffering from vitreous haemorrhage. Patients often require at least two treatment sessions and many return for additional sessions due to persistent neovascularisation (Tremolada et al., 2012).

Recently, a number of different treatment modalities have emerged which have been used in combination with PRP in order to improve the effectiveness of PRP and reduce the associated side effects. Several of these studies have used the corticosteroid Triamcinolone as an adjunct to PRP for the treatment of PDR (Zacks and Johnson, 2005; Bandello et al., 2006; Zein et al., 2006).

3.2 Triamcinolone as an adjunct to PRP

Triamcinolone is a long-acting synthetic corticosteroid that is widely used to treat diabetic macular oedema. More recently it has increasingly been used as an adjunctive with PRP for the treatment of PDR and macular oedema (Lopez et al., 2012). A number of studies have demonstrated that the adjunctive use of triamcinolone with PRP leads to a higher rate of new vessel regression and reduced macular oedema compared to PRP alone (Zacks and Johnson, 2005; Bandello et al., 2006; Zein et al., 2006; Lopez et al., 2012)

One such study was performed by Zacks and Johnson (2005). The purpose of the study was to investigate the effects of intravitreal injection of triamcinolone acetonide (IVTA) in combination with PRP for patients who had clinically significant macular oedema and PDR. A total of four patients were included in the study and outcome measures included visual acuity before and after, presence of macular oedema and response of PDR to laser photocoagulation. The results of the study demonstrated that all patients maintained stable VA, showed improvement with regards to progression of macular oedema and showed a complete regression of neovascularisation. Moreover, there were no short term complications associated with IVTA or PRP use (Zacks and Johnson, 2005).

A similar study was carried out by Zein et al (2006) who investigated the role of IVTA as an adjunctive therapy to PRP in patients with both high-risk PDR and clinically significant macular oedema (CSME). A larger sample of 35 patients was used with a nine month follow up. The patients received PRP and a single injection of 4 mg of IVTA. An improvement in vision and a decrease or complete resolution of macular oedema was noted in both the IVTA group and laser group. More importantly, after the 9 month follow-up 100% of the eyes in the laser group and laser plus IVT group had shown regression or no further progression of new vessels. The results of the study indicated that the addition of IVTA to PRP may be useful in managing patients with both PDR and CSME (Zein et al., 2006).

A more recent prospective, comparative study performed by Bandello et al 2006 evaluated the effect of intravitreal triamcinolone injection plus PRP versus PRP alone in the treatment of PDR. A total number of nine patients with bilateral proliferative diabetic retinopathy were included in each group, with a twelve month follow up. The efficacy of each treatment was determined by the reduction of leakage area of the new vessels based on fluorescein angiography (FA). Regression of neovascularisation was observed in all eyes that were treated with laser therapy and IVT. After a period of one, six and nine months, a 74%, 84%, and 86% reduction of the leakage area was observed. A decrease in leakage from new vessels also occurred in the eyes treated with PRP alone throughout the entire follow-up period, but at a much slower rate. A reduction of 19%, 22%, and 33% of the leakage area was observed at three, six, and nine months. The study demonstrated that intravitreal injection of triamcinolone before PRP may be useful in improving the effects of PRP in eyes with proliferative diabetic retinopathy by reducing neovascularization and macular thickening (Bandello et al., 2006).

The results of the above studies are promising and indicate that intravitreal triamcinolone may play an important role as an adjunctive therapy to laser for the treatment of PDR. However, the studies have several limitations. The relatively small sample size especially with regards to the study performed by Zacks and colleagues 2005 where only 4 patients were tested on was a limiting factor. Furthermore, a relatively short duration of follow up was implemented in the above studies. Due to these limitations it is difficult to establish how effective triamcinolone really is. Further studies that overcome these limitations, with a larger sample size and longer duration of follow up are needed in order to assess the efficacy and safety of intravitreal triamcinolone injection as an adjunctive treatment to PRP in the treatment of PDR.

The use of PRP alone or in combination with other drugs such as triamcinolone induces significant side effects. This was quite evident in these studies as drug-related side effects such as secondary glaucoma and the progression of cataract were commonly observed in the injected patients. (Zacks and Johnson, 2005; Bandello et al., 2006; Zein et al., 2006; Lopez et al., 2012).

With the above in mind, it is imperative that new effective therapeutic strategies are continually searched for with an aim of improving vision without causing tissue destruction. Quite recently, alternative forms of treatments to PRP, such as anti-VEGFs, have been investigated as possible new therapies for PDR (Salam et al., 2011).

Before the efficacy of anti-VEGF treatments is discussed, it is imperative to understand why VEFG is such an appealing therapeutic target. The following section focuses on this aspect.

4.0 VEGF

The vascular endothelial growth factor (VEGF) is a pro-inflammatory glycoprotein that plays an important role in many physiological and pathological processes (Ferrara and Henzel, 1989). It belongs to a family of angiogenic growth factors, which include VEGF-A (VEGF), VEGF-B, VEGF-C, VEGF-D, VEGF-E and placental growth factor (Hoeben et al., 2004). VEGF-A referred to as simply VEGF is the major endothelial growth factor involved in the process of angiogenesis and vascular permeability (Ferrara and Henzel, 1989; Giuliari et al., 2010).

Angiogenesis is the process of new vessel formation from pre-existing ones. It is a physiological process that is essential for the growth and development of tissue and wound healing (Sullivan and Brekken, 2010; Risau, 1997). The problem arises when these blood vessels start to proliferate abnormally, leading to neovascularisation, a process that plays a key role in the pathogenesis of PDR (Giuliari et al., 2010). Studies have shown VEGF to be the primary factor involved in PDR (Tremolada et al., 2012).

VEGF levels have shown to be regulated by hypoxic conditions (Shweiki et al., 1992). Aiello and Cavallerano 1994 demonstrated increased levels of VEGF in the vitreous of patients with PDR, compared with patients with NPDR. It was also shown that PRP administration caused a reduction in VEGF levels in patients with PDR (Aiello et al., 1994). A study performed by Robinson et al 1996 revealed that blocking VEGF hindered the development of PDR in ischeamic mouse models of retinopathy (Robinson et al., 1996). In another study it was shown that intravitreal VEGF injections induced iris neovascularization and retinopathy in non-human primates (Tolentino et al., 2002).

These studies drew the attention of researchers and as a result VEGF began to be seen as a viable therapeutic target for the treatment of PDR. With the recent success of anti-VEGF therapy for ARMD (MARINA and ANCHOR studies) it was hoped that similar results could be translated for anti-VEGF treatment in PDR.

The anti-VEGFs currently under investigation are Macugen (Pegaptanib sodium), Lucentis (Ranibizumab), and Avastin (Bevacizumab). Amongst these, Avastin has been the most extensively used molecule for the treatment of PDR (Tremolada et al 2012).

4.1 Anti-VEGFs

4.1.2 Macugen

Macugen also known as Pegaptanib sodium is a nuclease resistant, 28-nucleotide RNA aptamer that binds specifically to the VEGF-A165 isomer, a major pathological VEGF protein found in the eye (Ng et al., 2006). Pegaptanib binds to the cellular receptors of this isomer at high affinity, thereby inhibiting initiation of downstream signalling events (Gragoudas et al., 2004).

Macugen is currently licensed for the treatment of wet AMD. It received FDA approval for the treatment of wet AMD in December 2004 as a result of the VISION study (Group et al., 2006). The study demonstrated the efficacy of intravitreal pegaptanib in the treatment of neovascular age-related macular degeneration (AMD) (Group et al., 2006). In terms of its effect on PDR, there is very little literature currently available that addresses this question. A fairly recent prospective, randomised controlled study performed by Gonzalez et al 2009 aimed to clarify the efficacy of intravitreal pegaptanib versus PRP in the treatment of active PDR (Gonzalez et al., 2009). Twenty subjects with active PDR were randomly assigned to receive treatment either with 30mg of intravitreal Pegatapnib every 6 weeks for 30 weeks, or with PRP laser. The results showed that intravitreal pegaptanib (IVP) was able to induce regression of neovascularised retinal vessels within three weeks in 90% of treated patients. Furthermore by week 12, a complete regression of all patients treated with IVP could be seen and this was maintained through to week 36. A mild to moderate ocular adverse effects were reported (Gonzalez et al., 2009). Other smaller scale studies such as the one performed by Mendrios et al 2009 have also shown pegaptanib to be beneficial for the treatment of PDR (Mendrinos et al., 2009).

4.1.3 Lucentis

Lucentis also known as Ranibizumab is an engineered, humanized, recombinant antibody fragment (Fab) that is active against all isoforms of VEGF-A. It was approved by the FDA for the treatment of wet AMD in the year 2006 (Rosenfeld et al., 2006). It has a much shorter half-life as compared to other anti-VEGF agents due to its small antibody fragment which lacks the Fc domain (Rosenfeld et al., 2006; Hussain et al., 2007).

Several studies have demonstrated Lucentis to be effective in the treatment of diabetic maculopathy (Chun et al., 2006; Nguyen et al 2006). Unfortunately as with Macugen, there is a very limited amount of literature available that focuses on its efficacy for the treatment of PDR. This may be due to the high cost associated with these molecules (Giuliari et al., 2010).

The current literature indicates a lack of finished reports on the effect of ranibizumab on PDR (Jardeleza and Miller, 2009). In actual fact, we are still awaiting the results of a randomized prospective controlled trial study undertaken by ‘The Diabetic Retinopathy Clinical Research Network’ (DRCRnet). The aim of the study was to determine whether intravitreal ranibizumab or intravitreal triamcinolone 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. Approximately 381 subjects were enrolled into the study and were randomly assigned to receiving either 0.5mg ranibizumab or 4mg triamcinolone. The main efficacy measure was the visual acuity at week 14. Secondary efficacy measures included changes in retinal thickness, presence and extent of new vessels on fundus photographs, vitreous haemorrhage and requirement of additional sessions of scatter photocoagulation due to worsening of PDR before the initial 14 week visit completion. The results of this study are eagerly awaited by the scientific community (Available at: http://drcrnet.jaeb.org/ Accessed: March 11, 2013 as cited by Salam et al., 2011).

4.1.4 Avastin

Avastin (Bevacizumab) is a full length recombinant humanized murine monoclonal antibody active against all isoforms of VEGF-A (Salam et al., 2011). The amino acid sequence of this antibody is 93% of human origin and 7% murine. It is a fairly large molecule with a molecular weight of 148 kDa. It confers an advantage over other anti-VEGF in that it has two times the half-life of Lucentis, with a prolonged effect on retinal neovascularisation (Abdallah and Fawzi, 2009). Avastin is FDA-approved for the treatment of metastatic colorectal, breast and lung cancer (Cohen et al., 2007a; Cohen et al 2007b). The drug is not currently licensed for intraocular use, but nonetheless it remains the most used and popular among all anti-VEGF agents (Salam et al., 2011). Numerous studies have investigated the role of Avastin in patients with DME, as well as advanced PDR requiring vitrectomy due to vitreous haemorrhage and TRD complications. Moreover, avastin has been used in cases of neovascular glaucoma. However, the use of this drug for the purposes mentioned above is beyond the scope of this dissertation. The following section discusses the use of Avastin for PDR either alone or in combination with PRP.

4.1.4.1 Avastin for the treatment of PDR

Avery et al (2006) reported the effect of avastin for the treatment of patients with PDR. Data was presented for 45 eyes of 32 patients. Patients received a dose ranging from 6.2 μg to 1.25 mg of intravitreal avastin. Absence of leakage or a reduction of leakage was observed in 100% of the eyes. The study demonstrated that Avastin was well tolerated at all doses and effective in reducing neovascularisation of vessels in patients with PDR. A study completed by Mirshahi et al (2008) forms a significant part of the literature with regards to Avastin and PRP treatment. Forty patients with high risk characteristic PDR were given PRP according to the ETDRS protocol. Subjects also received 1.25mg Avastin injection in one eye and a sham injection in the other eye that was used as a control. All participants were followed for a period of 16 weeks. At week six, 87.5% of eyes that were treated with Avastin and 25% of the sham treated group showed a complete regression of neovascularisation. However, at week 16 there was no difference between the two groups due to recurrence of PDR in the Avastin treated eyes. The study demonstrated that Avastin was effective in inhibiting the formation of new vessels. Nonetheless, the effects were short lived as a number of the treated eyes showed a recurrence of PDR. The study suggested alternative dosing schedules for further evaluation.

4.1.4.2 Effect of intravitreal avastin in PDR eyes resistant to PRP

Jorge et al (2006) investigated the effect of intravitreal Avastin in eyes with active PDR resistant to PRP. Intravitreal injection of 1.5 mg of avastin was given to 15 subjects who were followed for a period of 12 weeks. The best-corrected visual acuity (BCVA) improved considerably from 20/160 at baseline to approximately 20/125 at week 12. Furthermore, the mean area of new vessel leakage decreased significantly at weeks 1 and 12, whilst at week 6 no leakage was observed. The study suggests avastin may play an important role for the treatment of eyes with refractory PRD. However, further and larger studies are warranted to confirm the results of this study.

4.1.4.3 Avastin in combination with PRP vs. PRP alone

In a comparative study by Tonello et al (2008), the effects of PRP compared to PRP plus avastin was investigated in 30 patients with high risk PDR. A positive effect on the reduction of new vessel growth was observed in a short period of time. A reduction of neovascularisation could be seen in 3.78%, 6.8%, and 11.2% of patients who received PRP alone, after four, nine, and sixteen weeks. In contrast, in eyes receiving PRP and IVB, a reduction of neovascularisation was seen in 94.5%, 93.99%, and 60% after four, nine and sixteen weeks respectively. In another study, Cho et al (2009) when evaluating the efficacy of avastin (1.25 mg) as an adjunctive treatment to PRP for high-risk PDR patients, observed a significantly lower proportion of eyes that developed vitreous haemorrhage in the avastin plus PRP group compared to the PRP alone group. The above studies taken together showed that the adjunctive use of intravitreal avastin with PRP was more effective as compared to PRP alone in reducing neovascularisation of vessels. Furthermore, the study by Cho et al (2009) suggested that PRP in combination with avastin may reduce the risk of developing vitreous haemorrhage as compared to PRP alone.

A recent study performed by Lopez et al (2012) evaluated the efficacy of intravitreal triamcinolone (IVT) and bevacizumab (IVB) as adjunctive treatments to pan retinal photocoagulation (PRP) in patients with PDR. The main goal of the study was to evaluate the regression of the new vessels (NVs). New Vessels were considered to have regressed when no leakage was observed during any phase of the angiogram. A six month follow up period was used to evaluate the regression of the new vessels. At the end of the 6-month follow-up period, adjunctive use of both triamcinolone and bevacizumab with PRP lead to a greater reduction of active NV than PRP alone. There was a significant difference in active NV between the use of PRP alone and its use in combination with IVT and IVb. With PRP alone, 27.5% of NV were considered to have regressed, compared to 74.4% with PRP plus IVT?, and 76.8% with the combination of PRP plus IVB respectively. Interestingly, no significant differences were observed between the IVT and IVB groups.

The latter combined treatments of PRP with IVT or IVB also showed a favourable control of retinopathy. A reduction in the severity of retinopathy was observed in 65% of the patients that received PRP plus IVT and 79% in those that received PRP plus IBV?. In contrast, only 53% of patient that received PRP alone showed a reduction in the severity of retinopathy. Furthermore, in the combined groups the severity of the retinopathy did not worsen in any of the eyes whereas eyes treated with PRP alone showed a worsening of retinopathy in 15% of the patients.

The study carried out by Lopez et al (2012) seems to be to date, the first to use both bevacizumab and triamcinolone and compare the effects of these drugs to each other and against PRP in ‘naive eyes’. To summarise the study, adjunct use of intravitreal triamcinolone or bevacizumab treatment was relatively safe and lead to better control of retinopathy in patients with PDR. The data obtained from the study also seemed to suggest that the higher the severity of retinopathy, the more effective the combined treatments. The results of the study were promising, however further studies are needed in order to replicate and consolidate the results of this study.

4.1.5 Limitations and side effects of Anti-VEGF Treatment

Despite the promising effects of anti-VEGFs, a number of limitations and side effects are associated with the use of these drugs. A major limitation that has been reported is the recurrence of neovascularisation of retinal vessels, ranging between 2 weeks (Avery, 2006) to 3 months after administration of anti-VEGFs (Spaide and Fisher, 2006; Thew, 2009).

Anti-VEGF agents may induce systemic side effects by entering the systemic circulation 93–95 which may lead to systemic hypertension, thrombosis and further cardiovascular complications (Gragoudas et al., 2004; Gragoudas et al., 2004; Roth et al., 2009). Kumar et al (2010) suggested a careful monitoring for the use of anti-VEGF agents in women of child bearing age. Patients with PDR tend to be on average considerably younger as compared to patients with ARMD, therefore a potential risk of carcinogenicity, teratogenicity and impairment of fertility may be associated with the use of anti-VEGF agents in these individuals. However, further studies are required in order to substantiate these systemic side effects particularly in diabetic subjects with significant vascular complications (Salam et al., 2011).

Avastin has shown to cause tractional retinal detachment (TRD) in patients with severe PDR (Moradian et al., 2008). Risk factors in developing TRD following use of avastin includes patients with poorly controlled diabetes and PDR resistant to PRP (Ahmadieh et al., 2009). Other side effects include uveitis and a transient rise in IOP levels (Wu et al., 2008; Ladas et al., 2009). Furthermore, Shima et al (2008) reported serious side effects such as endophthalmitis, lens injury, retinal pigment epithelial tear and acute visual loss.

With regards to macugen and Lucentis, not as many side effects have been reported. This may be due to the fact that their use has been limited for the treatment of PDR. Krishnan et al (2009) reported two cases of TRD after intravitreal pegaptanib (0.3mg/0.9 ml) treatment. A major study that used macugen to treat patients with AMD (VISION trial) found no systemic side effects associated with macugen treatment (Group et al., 2006; Singerman et al., 2008). Similarly, two important studies (Rosenfeld et al., 2006a; Brown et al., 2006) using intravitreal Lucentis to treat AMD and reported no systemic adverse effects with ranibizumab.

5.0 Discussion

The gold standard for treatment of PDR is PRP, mainly because it was shown to provide long term control of PDR as shown in two major clinical trials in ophthalmology, the DRS and EDTRS study, respectively (1981; 1991). These clinical trials demonstrated the efficacy of PRP for the treatment of PDR on a large scale and therefore laid down the foundation for this treatment. Studies such as the one performed by Vander et al (1991) further reinforced the effectiveness of PRP. However, although PRP was shown to be effective in preventing severe vision loss in patients with PDR, an earlier study by Doft and Blankenship revealed extensive retinal regression of new vessels could take a few weeks following PRP treatment. Moreover, new vessel growth could be seen in up to one third of cases despite initial PRP treatment (Doft and Blankenship, 1982).

PRP treatment is associated with significant ocular side effects (see section 4.1.5). In order to minimise these associated complications and improve the effectiveness of PRP, several studies used the corticosteroid triamcinolone as an adjunctive with PRP for the treatment of PDR. The results of these studies were encouraging. These studies showed triamcinolone in combination with PRP lead to a higher rate of new vessel regression and reduced macular oedema compared to PRP alone (Zacks and Johnson, 2005; Bandello et al., 2006; Zein et al., 2006; Lopez et al., 2012). Nonetheless, while the studies indicated a positive role for intravitreal triamcinolone as an adjunctive therapy to laser for the treatment of PDR, the studies had several drawbacks and limitations. The relatively short sample size especially with regards to the study performed by Zacks et al 2005 where only 4 patients were tested on was a limiting factor. Furthermore, a relatively short duration of follow up was implemented in the above studies. Due to these limitations it is difficult to establish how effective the use of triamcinolone as an adjunct with PRP really is. Further studies that overcome these limitations, with a larger sample size and longer duration of follow up are needed in order to address this question.

The use of PRP is limited in only alleviating the pathogenic process of PDR without affecting or addressing the fundamental source of the problem which lies within the pathophysiology of the disease. VEGF plays a fundamental role in the pathophysiology of PDR. It is a key component during the angiogenic process and has been shown to cause neovascularisation of retinal vessels during PDR (Willard and Herman, 2012). Anti-VEGFS were recently investigated as a treatment for PDR. It was hoped that by targeting the underlying cause of the disease, this form of therapeutic intervention would therefore be more useful in halting the progression and complications associated with PDR.

In this dissertation, we reviewed the studies that evaluated the role of the anti-VEGF agents Macugen, Lucentis and Avastin for the treatment of PDR. The current literature revealed only 2 small scale studies that assessed Macugen for the treatment of PDR (Gonzalez et al., 2009 Mendrinos et al., 2009). Furthermore, there was a lack of finished reports on the effects of Lucentis on PDR. Much of the information from these agents comes from their use and study of age-related macular degeneration (ARMD). The study performed by Gonzalez et al (2009) was promising, however further studies are needed to fully evaluate the role of Macugen and Lucentis in the treatment of PDR.

With regards to avastin, it was the most popular choice of the anti-VEGFs, perhaps due to its availability and low cost. The studies demonstrated that avastin whether used alone (Avery et al, Mirshahi et al., 2008; Jorge et al., 2006) or in combination with PRP (Tonello et al., 2008; Cho et al., 2009; Lopez et al., 2012) was beneficial in the treatment of PDR. Avastin was shown to inhibit or reduce retinal neovascularization and other proliferative complications in patients with high-risk or advanced stages of PDR.

The criteria used to define regression of new vessels differed between the studies. A reduction in leakage does not necessarily mean a complete inhibition of growth of these vessels, as these less active vessels can still cause complications such as vitreous haemorrhages or tractional retinal detachment. Therefore, it is important to have a definitive and restrictive criterion, which in turn provides a more useful assessment of the results obtained. Nevertheless, changes in the leakage area before and after treatment was provided by all of the above studies, therefore we can be confident with the results of the studies in providing objective data in terms of the regression of the new vessels. Another point to consider is the endpoint for evaluating the effectiveness of anti-VEGF treatments. The standard average endpoint to determine the effect of a treatment is normally considered as 6 months. Unfortunately, very few studies included a 6 months follow up. With the above in mind, it is difficult to directly compare the studies due to the varying study designs and evaluation criterion between the studies. In addition, the dosage of avastin varied between the studies. In a retrospective case series Avery et al. (2006) using doses of 6.2 μg to 1.25 mg noted rapid regression of retinal neovascularisation at all range of doses and found there was not much difference between the effects of various doses. On the other hand, Arevalo et al. (2009) using doses of 1.25 mg and 2.5 mg reported that the 2.5-mg dosage was more potent in inhibiting new vessel growth as compared to the 1.25 mg dose in naïve eyes. Therefore, it is difficult to establish what the optimal dose is for avastin. Despite this, generally, the avastin dose administered in most of the studies was 1.25mg, and it was effective in causing regression of new vessels (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).

The studies demonstrated that anti-VEGFs in particular avastin seem promising agents for the treatment of PDR, especially with regards to inhibiting neovascularisation of retinal vessels. However, the use of anti-VEGFs has been limited to adjunctive therapies for PDR, due to their short duration of effect and its association with adverse systemic and ocular side effects. Therefore caution is warranted until the safety and efficacy of these drugs has been fully established. The studies demonstrated the use of anti-VEGFs in combination with PRP yielded promising results and perhaps this is the way forward in managing PDR. However, further prospective randomised studies with larger sample sizes and longer duration of follow up are needed to ascertain this. A through literature search revealed that most of the studies have used anti-VEGFs for DME, for high risk PDR in combination with vitrectomy or for complications such as neovascular glaucoma. Only a few studies have tested the efficacy of these agents for the treatment of high-risk PDR, which is discussed in this dissertation. What seems to be lacking from the current literature are studies evaluating the effectiveness of anti-VEGFs in patients without high -risk PDR characteristics. It is hoped this gap in the literature is filled in the foreseeable future.

Conclusion

In conclusion, it is evident that PRP is still considered as the gold standard treatment for PDR due to its remarkable durability and effectiveness in proving long term control of PDR. Nonetheless, anti-VEGF therapy is rapidly entering the scene. Whether the role of anti-VEGFs for the treatment of PDR continues to expand in the future remains to be seen. Further studies evaluating the efficacy and safety of these drugs in the near future will certainly play a part in contributing to the success of these drugs. PDR is a complex condition and can lead to complications such as vitreous haemorrhage and tractional detachment. Therefore, no one therapy is likely to be perfect. With the further understanding of the pathogenicity of PDR, new treatments are expected to emerge. The future for the treatment and management of PDR certainly looks bright.