Retinal Neovascularization

Jason Hsu • Allen C. Ho

Introduction

Until recently, laser panretinal photocoagulation (PRP) has been the standard for treatment of patients with proliferative diabetic retinopathy (PDR) in order to reduce the risk of vision loss. The Diabetic Retinopathy Study (DRS) confirmed that PRP was associated with a 50% reduction in the risk of severe visual loss (visual acuity < 5/200) compared to no treatment.^1,2,3 The Early Treatment of Diabetic Retinopathy Study (ETDRS) further defined the appropriate timing for initiation of PRP.⁴ However, laser PRP can be uncomfortable for patients and is not without its potential risks, including visual field constriction, night blindness, macular edema, development or progression of tractional retinal detachment (TRD), and choroidal detachment with possible acute angle closure glaucoma. In addition, only about 60% of patients with PDR seem to respond to PRP laser treatment with regression of neovascularization within 3 months.⁵ As a result, many patients require additional laser treatment and about 4.5% ultimately need pars plana vitrectomy despite PRP.⁶

The role of growth factors in the development of retinovascular diseases was first proposed by Michaelson⁷ in 1948. It was not until the discovery and cloning of vascular endothelial growth factor (VEGF) in 1989 and the ensuing development of anti-VEGF antibodies that the key role of this factor in retinal neovascularization was realized.^8,9 VEGF levels have been shown to correlate with the severity of PDR and decrease following PRP.^10,11 Injection of VEGF in a primate model produced a retinopathy similar to diabetic retinopathy and even resulted in iris neovascularization.^12,13 Blockage of VEGF was associated with inhibition of iris neovascularization and suppression of retinal neovascularization in primates.^14,15 Given these findings, anti-VEGF treatments have been hypothesized as an alternative treatment for retinal neovascularization.

Anti-Vegf Therapies for Neovascularization in Proliferative Diabetic Retinopathy

Pegaptanib

Pegaptanib sodium (Macugen; Eyetech Pharmaceuticals, Inc.; New York, NY and Pfizer Inc.; New York, NY) is an anti-VEGF aptamer that specifically blocks the 165 isoform of VEGF, which is believed to be the predominant isoform responsible for pathological neovascularization. It was the first treatment of its kind approved for intraocular injection by the Food and Drug Administration in the treatment of neovascular age-related macular degeneration. A phase 2 study with pegaptanib was also performed in 172 patients with diabetic macular edema and found that intravitreal injections every 6 weeks for 12 to 30 weeks resulted in better visual acuity outcomes, decreased central retinal thickness, and a reduced need for focal/grid laser at 36 weeks compared to sham injections.¹⁶ At baseline, 19 of these subjects were also noted to have retinal neovascularization. This provided an opportunity to explore the effects of pegaptanib sodium on these patients in a retrospective fashion. Three of the nineteen patients were excluded from this review since one had PRP performed 13 days before randomization and two did not have follow-up photographs. Of the remaining 16 subjects, 8 had prior PRP at least 26 weeks before study entry, 1 had PRP 14 weeks before enrollment, and 1 was treated with PRP 89 days after study enrollment.

Thirteen of the sixteen patients were randomized to the pegaptanib group. Of these, eight (including the one patient who received PRP after study enrollment) showed regression or absence of neovascularization by week 36. None of the three patients in the sham group showed regression. Following cessation of pegaptanib, three of the eight patients who originally showed regression of neovascularization had progression by week 52.

This study was the first report documenting regression of neovascularization in patients with PDR who were given intravitreal anti-VEGF therapy. Although the number of cases was small, they provided the initial evidence for a definitive role of VEGF in retinal neovascularization and confirmed experimental observations in laboratory studies.¹⁷ While spontaneous regression of retinal neovascularization has been reported, such cases are extremely rare.¹⁸ The fact that 62% of the patients with baseline retinal neovascularization who received pegaptanib showed regression in addition to the observation that recurrence of the new vessels occurred in three of the eight cases after discontinuation of the injections seems to suggest a causal relationship.

Bevacizumab

Bevacizumab (Avastin; Genentech, Inc., South San Francisco, California) is a full-length recombinant humanized monoclonal antibody directed against all isoforms of VEGF and approved by the Food and Drug Administration for the treatment of metastatic colorectal cancer.^19,20,21 Shortly after intravitreal bevacizumab was reported to have beneficial effects in patients with neovascular age-related macular degeneration,^22,23 several small case series emerged describing the effects of this treatment on patients with neovascularization due to PDR.

Avery demonstrated the rapidity of regression of iris and retinal neovascularization in a 60-year-old woman who had prior partial PRP 18 months before.²⁴ One week after intravitreal bevacizumab, both the iris rubeosis and retinal neovascularization were clinically regressed with resolution of neovascular leakage on fluorescein angiography.iedlander and Welch²⁵ described a 36-year-old patient with advanced PDR and macular edema who received an intravitreal injection of 1.25-mg bevacizumab. Initial visual acuity was 20/100. Eight days later, his visual acuity had improved to 20/40 and the neovascular vessels were no longer apparent. Isaacs and Barry reported a similar result in an asymptomatic 70-year-old patient with neovascularization of the disc (NVD) whose visual acuity was 20/30. Following a single 1.25-mg injection of intravitreal bevacizumab, complete resolution of the NVD was noted at the 1 month follow-up visit and the visual acuity remained stable.²⁶ Fluorescein angiography showed no evidence of neovascular leakage. No clinical evidence of recurrence of the NVD was seen at the 2 month follow-up. Figure 14.1 shows one of our patients who presented with NVD due to PDR. He received 1.25 mg of intravitreal bevacizumab and returned 2 weeks later with no clinical evidence of NVD (Fig. 14.2).

FIGURE 14.1. Color photograph demonstrating disc neovascularization in a diabetic patient prior to intravitreal bevacizumab.

FIGURE 14.2. Color photograph 2 weeks after intravitreal bevacizumab showing marked clinical regression of the disc neovascularization.

Mason et al.²⁷ described three patients who demonstrated rapid regression of neovascularization following a single 1-mg intravitreal bevacizumab injection. One case with prior PRP but active NVD and neovascularization elsewhere (NVE) showed complete regression by 3 weeks postinjection with no recurrence by last follow-up at 10 weeks. A second case with partial PRP presented with severe NVD and NVE. The neovascularization regressed within 2 weeks of an intravitreal bevacizumab injection. Additional PRP was delivered and the patient remained stable until last follow-up at 5 months. The final case presented with severe PDR with a subhyaloid hemorrhage involving the macula. Following intravitreal bevacizumab, regression of the NVD and NVE was noted within 3 weeks. One potential benefit of such rapid regression of neovascularization might be prevention of vitreous hemorrhage (VH).

Avery et al.²⁸ confirmed a biologic effect of intravitreal bevacizumab on regression of retinal and iris neovascularization due to diabetes mellitus. In this retrospective case series, 45 eyes of 32 patients with retinal and/or iris neovascularization received a single dose of intravitreal bevacizumab. Follow-up was short-term, ranging from 1 to 14 weeks with a mean of 5 weeks. The majority of eyes (38 of 45) had received prior PRP. Various doses of intravitreal bevacizumab were tested with two eyes receiving 6.2 μg, five eyes receiving 12.5 μg, one eye receiving 62 μg, two eyes receiving 125 μg, two eyes receiving 625 μg, and 33 eyes receiving 1.25 mg.

All eyes demonstrated partial to complete reduction in leakage of the neovascularization on fluorescein angiography, even with the lowest dose tested. Of 26 eyes with NVD, complete resolution of angiographic leakage was seen in 19 eyes (73%). A fast clinical response was noted with leakage decreasing in as little as 24 hours after the injection. In several cases, the neovascularization seemed to regress with a reduction in the caliber and presence of neovascular vessel perfusion. Following the single injection, time to recurrence of angiographic leakage varied from 2 weeks to beyond 11 weeks. Interestingly, two cases had a mild decrease in leakage from retinal or iris neovascularization in the uninjected fellow eye, suggesting that the intravitreal dose may cross the blood-retinal barrier and reach therapeutic systemic levels. While no adverse events were seen in this short-term study, these findings suggest that systemic side effects may occur even with intravitreal injections and that lower doses may help mitigate the potential risk.

Jorge et al.²⁹ performed a prospective nonrandomized study of 15 eyes of 15 consecutive patients treated with 1.5 mg of intravitreal bevacizumab for active neovascularization from diabetic retinopathy that was refractory to laser treatment. Complete PRP had to be performed at least 4 months prior to enrollment in the study. Patients were followed for 12 weeks. Mean logMAR visual acuity improved significantly from a baseline of 0.90 (20/160) to 0.76 (20/125) at 1 week, 0.77 (20/125) at 6 weeks, and 0.77 (20/125) at 12 weeks (p < 0.05). The mean area of active neovascularization was quantified with fluorescein angiography and was found to decrease significantly from 27.79 mm² at baseline to 5.43 mm² 1 week after intravitreal bevacizumab (p < 0.05). Eleven of the fifteen eyes (74%) had decreased leakage while four eyes had no leakage at 1 week (Fig. 14.3). By week 6, no fluorescein leakage was seen in any eye (see Fig. 14.3). However, 12 weeks after the injection, some fluorescein leakage was noted with a mean area of 5.50 mm² (see Fig. 14.3), which was still significantly smaller compared to baseline (p < 0.05). Some amount of fluorescein leakage was seen in 14 of the 15 eyes (93%). However, no new or enlarged areas of active neovascularization were seen in any patient. No major adverse events were noted. This study was limited due to its small size and short follow-up but confirmed a transient effect of intravitreal bevacizumab on regression of neovascularization, which seems to begin to wear off between 6 and 12 weeks postinjection.

FIGURE 14.3. Red free, early-and late-phase fluorescein angiography from a diabetic patient with persistent active new vessels 5.5 months after panretinal laser photocoagulation (Case 1). (Top)Actively leaking new vessels at baseline; some fluorescein leakage also within the macula. (Top center)Marked decrease in fluorescein leakage from new vessels noted at baseline could be seen as early as 1 week after an intravitreal injection of 1.5 mg of bevacizumab. (Bottom center)At 6 weeks, some staining but no fluorescein leakage from new vessels and within the macula. (Bottom)Twelve weeks after injection, minimal fluorescein leakage is observed from new vessels noted at baseline. (Reproduced from Jorge, et al. Retina. 2006;26:1009, with permission.)

Another retrospective study of 44 eyes of 33 consecutive patients with retinal neovascularization from PDR who were treated with bevacizumab was performed by Arevalo et al.³⁰ Patients were followed for a mean of 28.4 weeks. Thirty-five eyes received 2.5 mg of intravitreal bevacizumab while the remaining nine eyes received 1.25 mg. Thirty-three eyes had prior PRP. Mean baseline visual acuity was logMAR 1.21 (20/300), and the final visual acuity was logMAR 0.70 (approximately 20/100). Twelve eyes (27.3%) had remained stable, 29 eyes (65.9%) had improved by two or more ETDRS lines, and 3 eyes (6.8%) had decreased by two or more ETDRS lines.

Twenty-seven eyes (61.4%) had total regression of the neovascularization by fundus exam and absence of leakage on fluorescein angiography. An additional 15 eyes (34.1%) had partial regression whereas only 2 eyes (4.5%) demonstrated no regression. Of the eyes with no regression, both had been previously treated with PRP. One eye had received 1.25 mg of intravitreal bevacizumab and progressed to TRD. The second eye developed VH after 2.5 mg of intravitreal bevacizumab. Regression of neovascularization was seen in some eyes as soon as 7 to 15 days after intravitreal bevacizumab. The authors found that the 2.5-mg dose appeared to be more effective than the 1.25-mg dose in inducing complete regression of neovascularization (p = 0.01).

Recurrence of neovascularization was seen in 21 eyes (47.7%) at a mean of 12.4 weeks (range = 4–34 weeks) necessitating a second injection. Seven eyes recurred after the second injection at a mean of 17.3 weeks (range = 11–22 weeks) and required a third injection. No local or systemic adverse events were reported over 6 months of follow-up.

As in prior studies, the authors felt that bevacizumab induces faster regression of neovascularization compared to PRP. Due to the longer time to regression with PRP, which is usually on the order of weeks, VH can occur and induce visual loss or prevent completion of the laser treatment. Therefore, bevacizumab may offer multiple benefits including prevention of VH, longer intervals between PRP sessions to lower the risk of complications, and allowing more selective use of PRP.

Minella et al.³¹ reported their results of an interventional case series of 15 eyes from 10 patients with bilateral PDR who received intravitreal injections of 1.25-mg bevacizumab. Thirteen eyes had severe PDR with active neovascularization, and two eyes had recurrent VH. They chose to include only patients who had a hemoglobin A1c < 8.5%. Some patients included had prior PRP or focal laser therapy. The authors performed quantitative planimetric analysis (QPA) of neovascular area based on the fluorescein angiogram and confirmed a significant reduction from 10.15 mm² at baseline to 1.15 mm² at month 1 postinjection (p = 0.01). PRP was performed at least 30 days after the initial injection. At 3 months follow-up, the QPA of neovascular area remained stable at 1.07 mm². Of eight eyes with 9 months follow-up, the QPA was maintained at 1.28 mm². The two eyes with recurrent VH showed both rapid resolution as well as regression of the neovascularization following intravitreal bevacizumab. No systemic or local adverse events were noted.

Bevacizumab Versus PRP Laser

A randomized, prospective fellow-eye controlled clinical trial comparing standard PRP and PRP with concomitant intravitreal bevacizumab was performed by Mirshahi et al.³²

Eighty eyes of 40 patients with bilateral PDR exhibited high-risk characteristics as defined by the Diabetic Retinopathy Study (i.e., NVD greater than or equal to one-fourth to one-third disc area, any amount of NVD with vitreous or preretinal hemorrhage, or NVE greater than or equal to one-half disc area with preretinal or VH).³³ One eye of each patient was randomly assigned to receive a single 1.25 mg of intravitreal bevacizumab at the time of their first PRP session. All eyes received standard PRP (1,200–1,500 spots, 0.2 seconds duration, 1/2 spot size apart) in three sessions, 1 week apart. Patients were followed for at least 16 weeks. Exclusion criteria included uncontrolled hypertension, myocardial infarction, or cerebrovascular accident within the past 6 months, uncontrolled glaucoma, previous retinal photocoagulation of any kind, and presence of TRD.

At week 6, 35 of the 40 bevacizumab-treated eyes (87.5%) compared to only 10 of the 40 eyes (25%) in the sham group showed complete regression of neovascularization on fluorescein angiography (p < 0.005). All patients in the bevacizumab group had at least partial regression though 36 of the 40 patients in the sham group also had at least partial regression (with 26 having partial regression in addition to the 10 with complete regression). However, by week 16, complete regression was only seen in 25% of eyes for each group. Partial regression was noted in 28 eyes in the bevacizumab group and 26 eyes in the sham group. In the bevacizumab group, the strongest determinant of recurrence of neovascularization was the hemoglobin A1c, which was 1.5% higher in those that recurred compared to those that did not (p = 0.033). No adverse events were seen in the bevacizumab-treated eyes.

One problem with this fellow-eye controlled study is the report that intravitreal bevacizumab injections may have an effect on the fellow eye.²⁸ This may explain the relatively high number of patients in the PRP only group that had at least partial regression of neovascularization by week 6. Therefore, it is possible that the difference in regression of neovascularization between the two groups may have been even greater than reported. Nevertheless, this study helps confirm a rapid but transient biological effect of bevacizumab on regression of neovascularization. Despite concomitant PRP, 75% of patients who received bevacizumab still had recurrence of neovascularization at week 16. This suggests that PRP may take longer to induce a permanent downregulation in VEGF and as a result, patients may need repeat intravitreal injections. Alternatively, the initial PRP treatment may have been insufficient.

PRP alone Versus PRP + Bevacizumab

A prospective, randomized study comparing PRP plus 1.5 mg of intravitreal bevacizumab with PRP alone was conducted by Tonello et al.³⁴ on 30 eyes of 22 patients with high-risk PDR and no prior laser treatments. Patients were followed for 16 weeks. Eight patients with bilateral PDR were included with the eye having the worse best-corrected visual acuity (BCVA) being assigned to PRP plus bevacizumab. In the 15 eyes that received bevacizumab with PRP, the injection was given an hour after completion of the second PRP session at week 3 after initial presentation.

The area of active neovascularization was measured based on fluorescein angiography and was found to decrease significantly in the PRP plus bevacizumab group from 11.15 mm² at baseline to 0.62 mm² at week 4, 0.67 mm² at week 9 and 4.46 mm² at week 16. No significant change was seen in the PRP only group with a baseline area of 15.31 mm², 14.73 mm² at week 4, 14.26 mm² at week 9, and 13.58 mm² at week 16. Best-corrected visual acuity remained stable in both groups throughout the study at around 20/40. The authors admit that they were hoping to see a protective effect of bevacizumab on preventing macular edema after PRP. However, no patients in the PRP only group developed macular edema, which may have been related to the PRP protocol (not >800 shots at one treatment and spread over two treatments that were 2 weeks apart).

A transient effect of bevacizumab is again suggested by the results of this study with a mild increase in the area of neovascularization from the week 9 to 16 follow-up despite concomitant PRP. It is possible that this trend may have continued if further follow-up were available. In this particular study, no visual acuity benefit was seen and no complications such as VH or TRD occurred even in the PRP only group despite maintaining active neovascular vessels throughout the 4-month duration of the study. Larger studies with longer duration of follow-up will be necessary to determine if bevacizumab provides any additional clinical benefit to PRP alone other than rapid neovascular regression.

Cho et al.³⁵ conducted a similar prospective, randomized study on 41 eyes of 25 patients with high-risk PDR (Box 14.1). Patients were divided into groups based on presence of clinically significant macular edema (CSME) and the enrolled eye was then randomized to receive either PRP with 1.25 mg of intravitreal bevacizumab or PRP alone. All eyes with CSME received focal/grid laser treatment at the time of PRP. Patients with prior PRP or focal/grid laser as well as hemoglobin A1c exceeding 9.5% were excluded. Nineteen eyes had CSME while 22 eyes did not. Nineteen eyes were randomized to the PRP group and 22 eyes to the PRP plus bevacizumab group. Sixteen patients had bilateral high-risk PDR and had one eye randomized to receive PRP with the fellow eye receiving the PRP plus bevacizumab. For the eyes in the PRP plus bevacizumab group, the injection was delivered 1 week before starting PRP. PRP was delivered in three sessions separated by 1 week with each session involving 300 to 500 shots.

In the PRP only group, BCVA decreased significantly from a baseline of logMAR 0.23 (~20/34) to 0.29 (~20/39) at 3 months (p = 0.041). In the PRP plus bevacizumab group, no significant change in visual acuity was noted. Central macular thickness by optical coherence tomography (OCT) also decreased from a baseline of 295 to 240 μm at 1 month (p = 0.012) and 237 μm at 3 months (p = 0.008).

Looking at eyes that presented with CSME, there was no significant change in visual acuity during the 3-month study in either treatment group. However, a decrease in central macular thickness was noted on OCT from 359 μm at baseline to 268 μm at 1 month (p = 0.003) and 252 μm at 3 months (p = 0.001) in the PRP plus bevacizumab group.

In eyes without CSME at presentation, BCVA worsened in the PRP only group from a baseline logMAR 0.18 (about 20/30) to 0.26 (about 20/36) at 1 month (p = 0.047) and 0.30 (about 20/40) at 3 months (p = 0.011). This was correlated with increasing central macular thickness on OCT. No changes were seen in visual acuity or OCT thickness in the PRP plus bevacizumab group. Four patients developed increased proliferation and VH in the PRP only group. None of these complications were seen in the PRP plus bevacizumab group. No progression to TRD was seen in either group, and no major local or systemic adverse events were noted.

This study supports combination treatment with PRP and bevacizumab for eyes with high-risk PDR, especially in cases with no CSME at baseline, to prevent subsequent macular edema, which has been well described following PRP alone.^36,37 In addition, bevacizumab seemed to lower the risk of subsequent VH developing after PRP. However, the study size is small and the differences in mean visual acuity are also small. The authors admit that Snellen acuities were used rather than ETDRS protocol refractions to measure BCVA. Finally, the follow-up period was relatively short and it is possible that given more time the difference between the PRP only and the PRP plus bevacizumab groups may have disappeared with longer follow-up. Nevertheless, a short-term clinical benefit of bevacizumab may make this a useful adjunct.

While few reports have been published using pegaptanib for retinal neovascularization, they have not shown as dramatic a response compared to bevacizumab. This difference in clinical response may be due to bevacizumab’s activity against all isoforms of VEGF while pegaptanib only inactivates the VEGF¹⁶⁵ isoform.³⁸ No reports have been published to date involving ranibizumab (Lucentis; Genentech, Inc., South San Francisco, CA) for retinal neovascularization related to PDR. One of the primary goals in designing ranibizumab as a Fab fragment rather than a full-length antibody like bevacizumab is the theoretical improved retinal penetration due to the smaller size. Although this feature may be an important consideration for subretinal neovascularization such as in neovascular age-related macular degeneration, it does not have any advantages in PDR where the pathological neovascularization is preretinal in location. Given the longer predicted half-life of bevacizumab, it may have the overall advantage for treatment in these cases.³⁹

Anti-Vegf Therapies for Vitreous Hemorrhage in Proliferative Diabetic Retinopathy

Due to the rapid regression of retinal neovascularization with intravitreal bevacizumab, one of the major potential benefits has been purported to be prevention of VH. The next logical topic to explore is the effects of intravitreal bevacizumab in patients with PDR who present with VH already present. Spontaneous resolution of VH usually takes time in part due to continuous bleeding from active neovascularization. Prior to the availability of anti-VEGF therapies, the main options were observation with the hope that PRP can be performed as the hemorrhage begins to clear or surgical intervention to remove the blood with simultaneous PRP.

Anti-VEGF therapies cause regression of neovascular vessels and may decrease any further bleeding, thereby accelerating the rate of VH resolution. This may help decrease the need for vitrectomy. With improved media clarity, PRP laser can then be completed to ensure that the neovascular regression becomes more permanent.

Spaide and Fischer⁴⁰ initially reported two patients with VH from PDR who were treated with 1.25 mg of intravitreal bevacizumab. Both patients presented with dense VH that precluded PRP. The first patient was a 68-year-old woman with prior incomplete PRP due to nonclearing VH of several years. Her initial visual acuity was 20/60. A localized extramacular TRD was noted on B-scan ultrasound. One week postinjection, she had improved to 20/40 and showed regression of both the retinal neovascularization and VH. By 3 months postinjection, early signs of reperfusion of retinal neovascularization were noted on clinical exam and fluorescein angiography. An additional injection was given. No progression of the TRD was seen. The second patient was a 38-year-old man with VH and an extramacular TRD. His initial visual acuity was 20/70. One week postinjection, his visual acuity had improved to 20/50 with a reduction in VH. One month postinjection, he was 20/30 with little remaining VH. The fibrovascular proliferation appeared nearly regressed though some leakage was noted on fluorescein angiography. An additional injection was given, and by 1 week later, he had improved to 20/25. At this point, PRP was performed. No progression of the TRD was noted.

An interventional prospective case series of 38 eyes of 38 patients with active PDR who received one to three intravitreal injections of 1.25-mg bevacizumab was performed by Moradian et al.⁴¹ (Box 14.2). Eligible eyes had active neovascularization refractory to prior PRP and/or severe new VH precluding completion of PRP. The first group was given intravitreal bevacizumab at least 3 months after the last session of PRP. The second group was given intravitreal bevacizumab at least 1 month after the onset of VH. Reinjection could occur at intervals of 6 or 12 weeks based on surgeon discretion, if there was incomplete VH resolution and/or inadequate regression of neovascularization.

BOX 14.2 Intravitreal Bevacizumab in Patients with Vitreous Hemorrhage due to PDR

• Objective: To evaluate the effect of intravitreal bevacizumab in eyes with active proliferative diabetic retinopathy (PDR).
  
• Methods: An interventional prospective case series was performed on eyes with active PDR that were given one to three injections of 1.25-mg intravitreal bevacizumab.
  
• Results: Thirty-eight eyes of 38 patients were included and followed for 20 weeks. Thirty-two eyes had vitreous hemorrhage (VH) at baseline. VH resolved significantly after 1 week (p = 0.014), 12 weeks (p = 0.0001), and 20 weeks (p = 0.002).
  
• Conclusions: Intravitreal bevacizumab may induce VH resolution in patients with active PDR..

Source: Moradian S, Ahmadich H, Malihi M, et al. Intravitreal bevacizumab in active progressive proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol. 2008;246:1699–1705.

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