Retina Anti VEGF Agents in Retinal Disorders Current Scenario Charu Gupta MS Charu Gupta MS, Cyrus M. Shroff MD Shroff Eye Centre, New Delhi T is a group of proteins involved in the regulation of angiogenesis, lymphangiogenesis and vascular permeability. Blinding complications of retinal diseases like neovascular age related macular degeneration, diabetic retinopathy, vascular occlusions are mainly due to pathologic ocular angiogenesis. There was a major breakthrough by Ferrara neovascularization 1. agents for treatment of retinal diseases like neovascular age related macular degeneration, diabetic retinopathy, vascular occlusions has become the gold standard and has shown good results. With widespread availability and usage it is important to use these agents safely and judiciously. Properties of VEGF 1. Stimulates angiogenesis factor 3. Increases vascular permeability 5. Neuroprotective action Pathological role of VEGF psoriasis and rheumatoid arthritis. In the eye, it has a major role in most of the pathologic angiogenic conditions like: Anti-VEGF agents are: Anti-VEGF agents in retinal disorders various ocular conditions 2,3. The most common indications presently are: Anti VEGF agents in Age related macular degeneration Indications classic, minimally classic and occult lesions. 3. Extrafoveal lesions in combination with thermal laser treatment. www. dosonline.org l 33
Retina: Anti VEGF Agents in Retinal Disorders Current Scenario Pretreatment ( 5/60, N36) Post anti VEGF Monotherapy (6/12, N8) Figure 1: Pretreatment and Posttreatment FFA and OCT of a patient with predominantly classic CNVM. Patient received loading dose of Anti VEGF injection followed by 2 more injections on a PRN basis. Patient has been subsequently stable for 2 years after last injection antibody Ranibizumab In the treatment of Neovascular of predominantly Classic CHORoidal Neovasularization of patients lost fewer than 15 letters of visual acuity when treated with ranibizumab compared with approximately one third of patients treated with ranibizumab improved vision by gaining 15 or more letters compared with 5% of controls 2,4,5. Treatment Protocol was the standard treatment protocol. It undoubtedly was a very happy situation for both the doctor and patient. Trials were then conducted to see if the frequency of injection can be reduced with minimal or no compromise 6 and Treat and Extend 7 regimen have been designed to work out dosing schedules for ranibizumab so that a lesser number of injections are required in the maintenance phase without losing out on Based on clinical trials and the experience of treating retinal physicians an initial loading dose monthly injections for advocated for most patients. PrONTO trial Optical coherence tomography (OCT) is able to accurately detect the earliest manifestations of recurrent increased retinal thickening, appearance of intraretinal OCT changes were often evident even before visual acuity with intraocular ranibizumab), Rosenfeld and associates 34 l DOS Times - Vol. 20, No. 5 November, 2014
Retina then evaluated at monthly intervals using OCT for signs within the macula. In the 37 patients who completed the in visual acuity score was 10.7 letters. Baseline vision was maintained by 78% of patients, and improved by 15 letters but with the mean frequency of dosing reduced by more Treat and Extend Regimen (TER) recurrent exudation, multiple recurrences over time may 7 starts with monthly injections until the signs of exudation have resolved with The treatment interval is then sequentially lengthened by 1 to 2 weeks, as long as there are no signs of recurrent exudation, till a maximum of 12 weeks. When recurrent the treatment interval is again extended as explained above. The Treat and Extend regimen demonstrated favorable after initial loading dose to maintain visual gain seen in (Figure 1). Follow up those situations a decision is often taken to combine the Anti VEGF agents in CNVM due to other pathologies associated with These patients usually do not require a loading dose and plays an important role in an accurate diagnosis and follow up of the pathology. Anti VEGF agents in Diabetic retinopathy Indications 1. Diabetic macular edema often followed up diabetic retinopathy glaucoma. detachment so as to minimize intraoperative bleeding. It is important to rule out any retinal traction prior to cases of diabetic retinopathy. In cases of active proliferative diabetic retinopathy or iris neovascularization he found a rapid response to intravitreal bevacizumab 8. Though the biologic effect is transient, bevacizumab, may have an adjunctive role with pan retinal photocoagulation in cases with severe neovascularization and macular edema. Furthermore, they found that preoperative administration of intravitreal bevacizumab in severe cases of proliferative causing an involution of vessels. Ranibizumab and bevacizumab, have both been found visual acuity and reducing macular thickness, in a series of randomized and non randomized trials. Recent reports from contolled clinical trials: Read trial (Ranibizumab for Edema of the Macula in Diabetes), Resolve trial (Ranibizumab in Diabetic Macular Edema with Center www. dosonline.org l 35
Retina: Anti VEGF Agents in Retinal Disorders Current Scenario Diabetic macular Edema) have all found ranibizumab acuity and reducing macular thickness 9,10. Results of the phase III Restore trial showed that Ranibizumab alone and 53%, respectively) and ranibizumab + laser (22.9% and 44.9%) versus laser alone (8.2% and 23.6%). Treatment Protocol in combination with laser photocoagulation in the standardized. Complete metabolic workup with emphasis on good control of blood sugar levels, blood pressure and and OCT is done to plan out treatment and prognosticate. patients to check for regression of vessels or if there is a clinical suspicion of a new vessel developing. injections monthly to dry the macula and then focal laser photocoagulation is added. If macular edema recurs laser sitting. In cases with massive macular edema or intravitreal corticosteroids if there is no contraindication to the latter. Retinal venous occlusions Indications but with documented increase in macular edema. BRAVO and Cruise trial of ranibizumab injection compared with sham in patients In 397 patients randomized, the mean gain from baseline at month 6 was 16.6 letters in patients receiving 0.3 mg of ranibizumab, 18.3 letters in those receiving 0.5 mg, and 7.3 letters in those receiving sham injection. ranibizumab injection compared with sham in patients month 6 was 12.7 letters in patients who received 0.3 mg ranibizumab, 14.9 letters in patients who received 0.5 mg ranibizumab, and 0.8 letters in those who received sham injections. Treatment Protocol resolution of the macular edema which is predominantly 11. However, issue so very often multiple injections are required. Thorough systemic workup of the patient especially the haemorrhages clear. It is important to evaluate the macular edema and retinal perfusion status periodically. schedules. In practice, most physicians will probably give basis can be extended past 3 months without recurrence of edema, the physician will know the treatment can be stopped because there is no active drug in the eye after 3 months. In patients with persistent edema, however, treatment decide to add grid or sector laser photocoagulation. When is recommended to perform laser a week or so after the 36 l DOS Times - Vol. 20, No. 5 November, 2014
Retina be applied more precisely and at lower power in retinal is added if any neovascularisation develops and quite often earlier if extensive capillary nonperfusion are seen, though there is no study to validate this. VEGF Trap (Aflibercept) compared to ranibizumab 12. respectively. 94% and 95% of patients treated with 2mg as did 94% of patients treated with ranibizumab. In an from baseline was +8.4 letters at week 52 and +7.6 letters at week 96 with a mean 11.2 injections over the 2 years of study, including 4.2 injections in year 2. In eyes treated baseline was +8.7 letters at week 52 and +7.9 letters at week 96, with a mean of 16.5 injections over the two years result was also good. Decreased frequency of treatment while retaining the safety approved. The recommended dose is 2.0mg every 8 weeks after an induction period of 3 monthly injections. demonstrated in clinical trials in the management of group (n=35, 1.9 percent) compared with the ranibizumab group (n=2, 0.3 percent) and that the magnitude of this difference was especially noticeable when analyzing the oldest pool of patients. This could be attributed to the longer systemic half life. Potential side effects and problems management of macular degeneration, diabetic retinopathy and venous occlusive disease but ocular and systemic safety concerns do exist. Post Avastin Endophthalmitis Figure 2: Photo showing a patient with endophthalmitis who presented 3 days Post intravitreal Anti VEGF injection. Ocular Endophthalmitis is a concern in any intravitreal procedure. Multiple large retrospective studies have demonstrated an incidence of one out of every 5,000 injections (0.02%). virulent Streptococcal species as the causative organism. Severe eye pain, with or without decreased vision, in the most common ocular signs (Figure 2). Early vitrectomy is usually advisable. Strict injection protocol with prepping of ocular surface with povidone iodine is advocated worldwide. In the Indian scenario, administration of injection in the operation theatre under aseptic measures with pre and post injection antibiotics is preferred. The paucity of compounding pharmacies in India and practice of multiple use vials. There is also a potential risk for contamination of bevacizumab during the aliquoting process, during transportation from the pharmacy to the deviation from established protocols has led to widespread contamination of bevacizumab lots. It is important for physicians to become aware of their supplying pharmacy s procedures for the above and check with them regularly to www. dosonline.org l 37
Retina: Anti VEGF Agents in Retinal Disorders Current Scenario should be used within 2 weeks. (trace to 1+) as compared to the sham or photodynamic therapy group. Transient increase in intraocular pressure, post injection, was seen with all the drugs. The intraocular pressure usually returned to normal within a week. Sustained elevations in intraocular pressure elevation occurs in 3.5 percent to 11 percent of patients receiving retinal detachment have been reported. one cause of decreased vision in patients undergoing patients with unusually large (i.e., tall) pigment epithelial Systemic (bevacizumab) given to patients with colorectal cancer, can lead to life threatening complications such as gastro intestinal perforation, wound healing complication, haemorrhage, arterial thromboembolic events (stroke or heart attack), hypertension, proteinuria and congestive heart failure. However, patient receiving bevacizumab for eye conditions are healthier than cancer patients and receive a tiny fraction of the dose which is administered in these studies. However, there is compelling clinical trial subgroup analysis and pharmacokinetic data pointing to drugs. serious adverse events associated with bevacizumab compared with ranibizumab even though there was no recently demonstrated in their pharmacokinetic study that ranibizumab has a lower systemic exposure due accumulation, while ranibizumab did not. Clinical trials designed to answer this question will have to powered to detect a meaningful difference for these rare events. High risk groups 2. History of stroke 3. Recent cardiovascular intervention 4. Diabetics with uncontrolled hypertension and proteinuria dose (0.3mg) of Ranibizumab is preferred. Future trends The future of treatment of neovascular disease lies in making a drug or a combination of them which are effective with no short term or long term safety concerns and easily administered. Ocuserts and pellets for sustained release of done for steroids. References 1. Ferrara N, Houck K, Jakeman L, Leung DW. Molecular and biological properties of the vascular growth factor family of proteins. Endocr Rev 1992;13:18-32. 2. Heier JS. Treatment of neovascular age-related macular degeneration with ranibizumab. In: Peyman GA, Meffert SA, Conway MD (eds): Vitreoretinal Surgical Techniques. Informa UK Ltd, 2007; 652-57. 3. Avery RL,Pieramici DJ. Bevacizumab in the treatment of ocular disease. In: Peyman GA,Meffert SA,Conway MD (eds): Vitreoretinal Surgical Techniques. Informa UK Ltd, 2007; 658-65. 4. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for Neovascular Age-Related Macular Degeneration. N Engl J Med 2006;355:1419-31. 5. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus Engl J Med 2006;355:1432-44. 6. Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab (Lucentis) for neovascularage-related macular degeneration: year two of the PrONTO Study. Am J Ophthalmol 2009;148:43 58. 7. Gupta OP, Shienbaum G, Patel AH, et al. A Treat and Extend Regimen Using Ranibizumab for Neovascular Age-Related Macular Degeneration -Clinical and Economic Impact. Ophthalmology 2010;117:2134 40. 8. Avery RL, Pieramici DS, Rabena MD et al. Intravitreal bevacizumab in the treatment of proliferative diabetic retinopathy. Ophthalmology 2006;113:363-71. 9. Nguyen QD, Shah SM, Khwaja AA, et al Two-Year Outcomes of the Ranibizumab for Edema of the macula in Diabetes (READ-2) Study. Ophthalmology 2010;117:2146 51. 10. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;4:615-25. edema from central vein occlusion. Ophthalmic Surg Lasers Imaging 2005;36:336-9. 12. Bayer Healthcare and Regeneron initiate phase 3 global development. www.viva.vita.bayer healthcare.com. 38 l DOS Times - Vol. 20, No. 5 November, 2014