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  5. FP11 : Comparison of UWFFA Guided PASCAL TRP with Ranbizumab Vs Ranibizumab Alone for Macular...

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Dr. Siddhi Goel, G18495, Dr. Vinod Kumar, Dr. Raghav D. Ravani, Dr. Atul Kumar

Introduction:

Branch retinal vein occlusion (BRVO) is obstruction of the major retinal vein, which occurs most commonly at an arteriovenous crossing.Branch retinal vein occlusion occurs due to thrombosis of a branch of the central retinal vein resulting in retinal haemorrhages, cotton wool spots and varying amounts of retinal non-perfusion in the area drained by the occluded vessel. Macular edema is the commonest cause of vision loss, others being macular ischemia and sequelae of neovascularisation like vitreous haemorrhage, neovascular glaucoma and tractional retinal detachment.

Vascular endothelial growth factor (VEGF) is thought to play an important role in the pathogenesis of ME with BRVO.[1]Noma et al demonstrated that aqueous levels of VEGF and IL-6 were significantly elevated in patients of BRVO[2] compared to controls. A high level of VEGF produced by the ischemic retina exacerbates retinal vascular leakage and neovascularisation. Therefore, anti-VEGF drugs play a critical role in the treatment of ME with BRVO. Campochiaro et al demonstrated that intraocular injections of 0.3 mg or 0.5 mg Ranibizumab provided rapid, effective treatment for macular edema following BRVO.[3,4]

urrently, anti-VEGF is the gold standard treatment for management of macular edema in vein occlusions, especially BRVO. However, due to limited half-life,[5] single injection of anti-VEGF agents provides temporary relief with high chances of recurrence of macular edema and need for repeated injections. This adds on to the economic burden of treatment, increased number of hospital visits apart from the risk of repeated interventions such as endophthalmitis and retinal detachment. Thus, there is a need for a treatment option that may act as adjuvant to the current gold standard and help in decreasing the number of injections required.

Ultra-wide field imaging (Optos Tx200, Optos Inc.) is capable of capturinga 2000 field allowing for simultaneous view of the posterior pole, mid periphery and periphery,[6] In a study by Wessel et al[7] demonstrated that UWF angiography detected 3.9 times more areas of CNP than conventional angiography in patients with diabetic retinopathy. The peripheral CNP areas in the setting of BRVO can act as a continuous source of VEGF and may be the potential area of interest as their selective ablation by laser photocoagulation may reduce the continuous VEGF production and thus reduce the number of treatments with anti-VEGF agents. This concept of selective laser photocoagulation is known as TRP and has shown its utilisation in proliferative diabetic retinopathy.[8] We conducted this randomised clinical trial to determine whether targeted laser photocoagulation promotes resolution of macular edema, reduces the need for VEGF antagonists and improves visual outcomes in patients with BRVO.

Methods:

This is a prospective, randomised interventional study conducted at a tertiary eye care centre in North India.  33 eyes of 32 patients with BRVO presenting to the retina clinic were enrolled from May 2015 to July 2016. The study was conducted in accordance with the Declarations of Helsinki and informed consent was obtained from all the enrolled participants. Ethical clearance was obtained from the Institute ethics committee.

Patients with decreased visual acuity secondary to BRVO with macular edema were eligible for the study if they had a visual acuity measured by Snellen chartof 20/60 (logMAR- 0.477) to 20/400 (logMAR- 1.30) and macular edema with a central retinal thickness greater than 300 µm. Patients who were pregnant, had uncontrolled hypertension or diabetes, had macular ischemia, had sensitivity to sodium fluorescein, had received prior anti-VEGF injection or scatter laser photocoagulation, or had any other additional ocular diseases that could irreversibly compromise the visual acuity of the study eye were excluded from the study.

Patients underwent a comprehensive ophthalmologic examination that included visual acuity assessment using Early Treatment Diabetic Retinopathy Study (ETDRS) protocol (ETDRS Illuminated Cabinet, Netherlands), IOP using Goldmann’s applanation, slit-lamp bio microscopy using 90 D, Swept source optical coherence tomography (SS-OCT, DRI Triton, Topcon, Tokyo, Japan), Pelli Robson contrast sensitivity (Pelli-Robson Contrast Sensitivity Chart, Haag-Streit, UK), Humphrey visual fields (30-2 Swedish Interactive Threshold Algorithm; Humphrey Field Analyser Model 750i, Carl Zeiss Meditec Inc., Dublin, California), and UWF fluorescein angiography using Optos C200MA (Optos Plc, Dunfermline, Scotland).

The patients were randomized to 0.5 mg Ranibizumab only (RBZ group) (n=17) or Ranibizumab with Optos guided PASCAL laser (RBZ+TRP group) (n=16). Patients in both the groups received 3 loading injections at monthly intervals. RBZ+TRP group additionally underwent UWF fluorescein angiography guided PASCAL targeted photocoagulation at 1 week after the first injection. After the first three injections,the patients in both the groups were treated with 0.5 mg Ranibizumab according to pro re nata regimen if visual acuity <20/40 or CST > 300 µm. Patients in both the groups were followed up for a minimum of 9 months.

Optos FFA was done at baseline and 9 months for every patient (Fig. 1a). It was performed by a single trained optometrist and areas of CNP were delineated. CST was assessed by SS-OCT at each follow up visit at 1 month, 3 months, 6 months and 9 months. In the RBZ + TRP group, TRP of CNP areas was carried out by a single experienced retina specialist on day 7 of 1st injection. TRP was carried out using using Pattern Scan Laser (PASCAL, Topcon Medical Laser Systems, Santa Clara, CA, USA). Topical 0.5% Proparacaine was used to anaesthetize eyes prior to the procedure. Topical 0.5% Moxifloxacin was instilled at the end of the procedure. Capillary non-perfusion areas were selectively lasered using Pascal 4*4 array with 20 ms pulse duration using QuadrAspheric lens (Volk Optical Inc., OH, USA) with a magnification factor of 0.51 and retinal spot size of 200µm. Laser burns were applied to the CNP areas and at the junction of ischemic and non-ischemic areas, extending anteriorly up to ora serrata (Fig. 1b). The laser spots were placed 1 burn width apart and end point of laser was taken to be moderate grey burns.

The primary outcome parameters were mean change in best corrected visual acuity (BCVA) from the baseline at 9 months, mean decrease in central sub-foveal thickness (CST) as measured on serial SS-OCT scans and number of injections required. The secondary outcome parameters were change in mean deviation (HVF 30-2 SITA standard) and Pelli Robson contrast sensitivity.

Statistical analysis was performed using Strata (Version 12.1). For pre and post injection analysis, paired t- test was used to evaluate the changes in CST. For non- parametric data i.e. visual acuity, contrast sensitivity and mean deviation on visual fields, Wilcoxon signed-rank test was used. For intergroup analysis, two-sample t test was used for parametric data and Mann-Whitney test was done for non-parametric data. P values less than 0.05 were considered statistically significant.

Result: A total of 33 eyes were enrolled: 17 were randomised to the RBZ group and 16 to the RBZ+ TRP group. Both the groups were comparable in demography and baseline characteristics (Table1).

64% cases had superotemporal BRVO and 36% had inferotemporal BRVO.

Significant improvement in visual acuity was noted in both the groups (p=0.0003 and 0.0004 respectively). The average gain in ETDRS letters in RBZ group was 25.7 vs 23.38 in the RBZ+TRP group.  The difference between the 2 groups was however not significant (p=0.93) (Fig. 2). Similarly, significant decrease in CST was noted in both the groups (p<0.0001 in each group). The change in CST in RBZ group was 379.12 µm vs 253.75µm in the RBZ + TRP group, however the difference among the 2 groups was not significant. (p=0.06) (Fig. 3)

The mean number of injections required in RBZ group was 5.76±1.3 and RBZ+TRP group was 4.06±0.99. This was statistically significant (p=0.0006, Mann-Whitney test). The intraocular pressure(IOP) in both groups showed no significant change from baseline IOP (p=0.64 and p=0.177 respectively). Both the groups had significant improvement in contrast sensitivity (p<0.0001 in each group), however the difference among the 2 groups was again not statistically significant (p=0.62). Patients in both groups demonstrated significant improvement in mean deviation from baseline (p=0.008 and p=0.004). None of the patients showed disease progression, laser photocoagulation or injection related complications during the study period.

Discussion:

VEGF is a potent angiogenic factor produced by Muller cells of hypoxic retina[9] due to vascular occlusion related retinal ischemia leading to increased vascular permeability, leakage and neovascularization. These factors contribute to macular edema, which is the main cause of visual morbidity in patients with venous occlusions. Anti-VEGF agents are thus,the main stay for treatment of macular edema following BRVO. However multiple injections are required to maintain the effect. The need for repeated injections can be explained by the short vitreous half-life of 2.88 days of intravitreal Ranibizumab (Bakri SJ et al).[5] Studies done by Prasad et al have demonstrated a positive correlation with untreated non perfusion anterior to equator with macular edema and neovascularisation in cases of RVO.[10] Thus, untreated areas of retinal non-perfusion may be the source of continuous production of VEGF leading to recurrence of macular edema after intravitreal anti-VEGF injection. Furthermore, the size of retinal non-perfusion is correlated with the severity of macular edema.[11,12]Hence, treatment of these target areas of non-perfusion can reduce the production of VEGF and thereby decrease the number of anti-VEGF injections required.

In our study, both the groups showed similar improvement in terms of VA and CST. In addition, contrast sensitivity and visual field sensitivity improved significantly in both the groups. We hypothesize that anti-VEGF by decreasing the macular edema improves the macular function and thereby increases the contrast sensitivity. As also suggested by Muqit el al,[8]the improved visual field sensitivity after TRP could be attributed to reduction in retinal ischemia. The number of injections required was significantly reduced in the group where additional TRP was performed.

Similar results were demonstrated by Tomomatsu et al suggesting that TRP of non-perfusion areas reduced the amount of ME recurrence following intravitreal Bevacizumab compared to Bevacizumab alone.[13] However, our study differed in the protocol of treatment which involved monthly injections for first three months along with laser after 1st injection. We used Optos imaging that helps to document a larger area of peripheral CNP[7] could be targeted with laser. The anti-VEGF used in our study was Ranibizumab which has higher potency than Bevacizumab. The RELATE trial[14] on contrary, suggested that scatter photocoagulation does not reduce macular edema or treatment burden in patients with retinal vein occlusion. The study differed from our study in the treatment protocol. The laser photocoagulation in RELATE trial was performed after six months of anti-VEGF treatment, while it was performed in our study after the first injection itself. This could affect the number of injections as most number of treatments are usually done in first six months. The RELATE trial did not recruit treatment naïve eyes. The limitations of our study were a small sample size and relatively small follow up period. Longer follow up studies with larger sample size are required to assess the long-term benefit of added laser to Ranibizumab treated patients of BRVO.

To conclude targeted laser photocoagulation of peripheral CNP areas in BRVO with macular edema may decrease need for repeated anti-VEGF injections and injection related complications like endophthalmitis and retinal detachment while maintaining similar benefits in visual acuity, contrast sensitivity and visual fields. This may bring down the healthcare cost related to management of venous occlusions.

References:

  1. Campochiaro PA, Hafiz G, Shah SM, et al. Ranibizumab for macular edema due to retinal vein occlusions: implication of VEGF as a critical stimulator. Mol Ther J Am Soc Gene Ther. 2008 Apr;16(4):791–9.
  2. Noma H, Funatsu H, Yamasaki M, et al. Pathogenesis of macular edema with branch retinal vein occlusion and intraocular levels of vascular endothelial growth factor and interleukin-6. Am J Ophthalmol. 2005 Aug;140(2):256–61.
  3. Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010 Jun;117(6):1102–1112.
  4. Heier JS, Campochiaro PA, Yau L,et al. Ranibizumab for macular edema due to retinal vein occlusions: long-term follow-up in the HORIZON trial. Ophthalmology. 2012 Apr;119(4):802–9.
  5. Bakri SJ, Snyder MR, Reid JM, et al. Pharmacokinetics of intravitreal ranibizumab (Lucentis). Ophthalmology. 2007 Dec;114(12):2179–82.
  6. Manivannan A, Plskova J, Farrow A, et al. Ultra-wide-field fluorescein angiography of the ocular fundus. Am J Ophthalmol. 2005 Sep;140(3):525–7.
  7. Wessel MM, Aaker GD, Parlitsis G, et al. Ultra-wide-field angiography improves the detection and classification of diabetic retinopathy. Retina Phila Pa. 2012 Apr;32(4):785–91.
  8. Muqit MMK, Marcellino GR, Henson DB, et al. Optos-guided pattern scan laser (Pascal)-targeted retinal photocoagulation in proliferative diabetic retinopathy. Acta Ophthalmol (Copenh). 2013 May;91(3):251–8.
  9. Campochiaro PA, Bhisitkul RB, Shapiro H, et al. Vascular endothelial growth factor promotes progressive retinal nonperfusion in patients with retinal vein occlusion. Ophthalmology. 2013 Apr;120(4):795–802.
  10. Prasad PS, Oliver SCN, Coffee RE, et al. Ultra wide-field angiographic characteristics of branch retinal and hemicentral retinal vein occlusion. Ophthalmology. 2010 Apr;117(4):780–4.
  11. Singer MA, Tan CS, Surapaneni KR, et al. Targeted photocoagulation of peripheral ischemia to treat rebound edema. Clin Ophthalmol Auckl NZ. 2015;9:337–41.
  12. Tan CS, Chew MC, van Hemert J, et al. Measuring the precise area of peripheral retinal non-perfusion using ultra-widefield imaging and its correlation with the ischaemic index. Br J Ophthalmol. 2016 Feb;100(2):235–9.
  13. Tomomatsu Y, Tomomatsu T, Takamura Y, et al. Comparative study of combined bevacizumab/targeted photocoagulation vs bevacizumab alone for macular oedema in ischaemic branch retinal vein occlusions. Acta Ophthalmol (Copenh). 2016 May;94(3):e225-230.
  14. Campochiaro PA, Hafiz G, Mir TA, et al. Scatter Photocoagulation Does Not Reduce Macular Edema or Treatment Burden in Patients with Retinal Vein Occlusion: The RELATE Trial. Ophthalmology. 2015 Jul;122(7):1426–37.

 

 

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