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Branch Retinal Vein Occlusion Current understanding and approaches to treatment Prescribing information can be found on the last two slides August 2016 UKEYL08160072 August 2016 UKEYL08160072 1 About this slide deck • This slide deck is provided as a service to medicine by Bayer and is intended for educational use with healthcare professionals only • Prescribing information for EYLEA (aflibercept solution for injection) is at the end of the slide deck, and is also available in accompanying material. • Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard • Adverse events should also be reported to Bayer: Tel: 01635 563500; E-mail: [email protected] August 2016 UKEYL08160072 2 Acknowledgements The contribution of the following in the development of this resource is gratefully acknowledged: • Peter Addison, Consultant Ophthalmologist, Moorfields Eye Hospital NHS Trust • Sanjiv Bannerjee, Consultant Ophthalmologist, University Hospital Wales • Michael Briggs, Consultant Ophthalmologist, Spire Liverpool Hospital • Ben Burton, Consultant Ophthalmologist, James Paget University Hospital • Louise Downey, Consultant Ophthalmologist, Hull Royal Infirmary • Samer Elsherbiny, Consultant Ophthalmologist, Birmingham and Midland Eye Centre • Richard Gale, Consultant Ophthalmologist, York Teaching Hospital • Praveen Patel, Consultant Ophthalmologist, Moorfields Eye Hospital NHS Trust • Adam Ross, Consultant Ophthalmologist, Bristol Eye Hospital • Gavin Walters, Consultant Ophthalmologist, Harrogate District Hospital and York Hospital • Yit Yang, Consultant Ophthalmologist, Wolverhampton Eye Hospital and Visiting Professor, Aston University August 2016 UKEYL08160072 3 Discussion topics • Definition of retinal vein occlusion • Epidemiology of RVO • Vision loss in BRVO • Pathophysiology • Natural history • Clinical signs and imaging features • Initial management • Management of macular oedema • Management of other complications August 2016 UKEYL08160072 BRVO = branch retinal vein occlusion. 4 Background and epidemiology of BRVO August 2016 UKEYL08160072 August 2016 UKEYL08160072 5 RVO is an obstruction of one of the veins that drains blood away from the retina • The type of RVO depends on the location of the occlusion1 BRVO Occlusion of a branch retinal vein HRVO CRVO Occlusion of the superior/inferior branch of the central retinal vein Occlusion of the central retinal vein • In the literature, HRVO is defined as an RVO that involves two retinal quandrants2,3 BRVO = branch retinal vein occlusion; CRV = central retinal vein; CRVO = central retinal vein occlusion; HRVO = hemiretinal vein occlusion; RVO = retinal vein occlusion. 1. Kiire CA, Chong NV. BMJ. 2012;344:e499; 2. Campochiaro PA, et al. Ophthalmology. 2010;117:1102–1112.e1; 3. Campochiaro PA, et al. Ophthalmology. 2015;122(3):538–544; August 2016 UKEYL08160072 6 Common sites of retinal vein occlusion1 Blue arrow Point at which the central retinal vein exits the eye – a common site for CRVO Yellow arrow An arteriovenous crossing – a typical site for BRVO Image courtesy of Yit Yang. BRVO = branch retinal vein occlusion; CRVO = central retinal vein occlusion. 1. Kiire CA, Chong NV. BMJ. 2012;344:e499. August 2016 UKEYL08160072 7 RVO is a major cause of vision loss • RVO is the second most common sight-threatening retinal vascular disorder (after diabetic retinopathy)1 – RVO is unilateral in most patients2 – Can be severe2 Possible loss of vision to below driving standards3 As a result, most patients are willing to undergo invasive treatments1 • Sign of possible underlying systemic pathology2 RVO = retinal vein occlusion. August 2016 UKEYL08160072 1. Laouri M, et al. Eye. 2011;25:981–988; 2. Royal College of Ophthalmologists. Retinal Vein Occlusion Guidelines, 8 July 2015; 3. UK Government Driving Eyesight Rules. Available here: https://www.gov.uk/driving-eyesight-rules. Accessed March 2016. RVO puts a major burden on the patient’s life1 4.5 hours average appointment time 86% require monthly appointments 53% of patients need to take ≥1 day off work per appointment 73% of these require long-term monthly appointments 71% of patients require a carer’s assistance for appointments August 2016 UKEYL08160072 1. Sivaprasad S, Oyetunde S. Clin Ophthalmol. 2016;10:939–946. 9 Incidence of BRVO is greater than CRVO • Beaver Dam Study (n = 4068):1 – 15-year incidence of BRVO was 1.8% versus 0.5% for CRVO – Incidence similar in men and women (1.5% versus 2.1%) • Blue Mountains Eye Study (n = 3654):2 – 10-year incidence of BRVO was 1.2% versus 0.4% for CRVO – Incidence similar in men and women (2.0% versus 1.3%) • There are no specific UK incidence data August 2016 UKEYL08160072 1. Klein R, et al. Arch Ophthalmol. 2008;126:513–518; 2. Cugati S, et al. Arch Ophthalmol. 2006;124:726–732. 10 Incidence of RVO varies with age 15-year cumulative incidence of BRVO and CRVO BRVO Incidence, % CRVO Age, years August 2016 UKEYL08160072 1. Klein R, et al. Arch Ophthalmol. 2008;126:513–518. 11 Symptoms of BRVO • The main symptom of BRVO is blurring of central vision • Can be sudden or gradual • Normally painless Fundus photograph of BRVO prior to treatment Image courtesy of Yit Yang. 1. American Academy of Ophthalmology. Branch Retinal Vein Occlusion Symptoms. Available here: http://www.aao.org/eye-health/diseases/branch-retinal-vein-occlusion-symptoms. Accessed March 2016. August 2016 UKEYL08160072 12 Causes of vision loss in BRVO: Macular oedema1 OCT showing inferior temporal BRVO with secondary cystoid macular oedema Image courtesy of Louise Downey. BRVO = branch retinal vein occlusion; OCT = optical coherence tomography. 1. Ehlers JP, et al. Surv Ophthalmol. 2011;56:281–299. August 2016 UKEYL08160072 13 Causes of vision loss in BRVO: Intraretinal haemorrhage1 FFA mid phase showing supero-temporal BRVO with significant ischaemia and masking due to retinal haemorrhage (blue area). Arrow indicates likely point of occlusion Image courtesy of Louise Downey. BRVO = branch retinal vein occlusion. 1. Ehlers JP, et al. Surv Ophthalmol. 2011;56:281–299. August 2016 UKEYL08160072 14 Causes of vision loss in BRVO: Ischaemia and neovascularisation1,2 FFA of superior ischaemic (blue arrow) BRVO with neovascularisation (yellow arrow) Image courtesy of Ben Burton. BRVO = branch retinal vein occlusion; FFA = fundus fluorescein angiography. 1. Yuan A, et al. In: Ryan S, Schachat A, Wilkinson C, et al, eds. Retina. Philadelphia, PA: Elsevier; 2013; 2. Ehlers JP, et al. Surv Ophthalmol. 2011;56:281–299. August 2016 UKEYL08160072 15 BRVO can be ischaemic or non-ischaemic • Ischaemia can be macular or peripheral Colour fundus photograph and fluorescein angiography showing BRVO with macular ischaemia Fluorescein angiography showing BRVO with peripheral ischaemia August 2016 UKEYL08160072 Images courtesy of Peter Addison and Ben Burton. 16 Peripheral ischaemia can be defined in disc diameters or disc areas • No consensus on prevalence of BRVO with peripheral ischaemia because of varying definitions, measurement techniques, and patient samples1 Study Definition used BVOS2 >5 disc diameters of non-perfusion VIBRANT3 ≥10 disc areas of non-perfusion BRVO = branch retinal vein occlusion; 1. Hayreh SS, et al. Ophthalmology. 1983;90:488–506; 2. Branch Vein Occlusion Study Group. Arch Ophthalmol. 1986;104:34–41; 3. Campochiaro PA, et al. Ophthalmology. 2015;122(3):538–544. August 2016 UKEYL08160072 17 Background and epidemiology: Summary • BRVO is an occlusion of a branch retinal vein • Main vision-threatening complications are macular oedema, retinal ischaemia, and neovascularisation and its sequelae • Impact on vision depends on the location of the occlusion • BRVO can be classified as ischaemic or non-ischaemic • Incidence of BRVO is 1.2–1.8% – Patients are predominantly over the age of 55 years, but BRVO also affects the working-age population – There are no specific data for the UK August 2016 UKEYL08160072 BRVO = branch retinal vein occlusion. 18 Pathophysiology of BRVO August 2016 UKEYL08160072 August 2016 UKEYL08160072 19 Key risk factors for BRVO1 • Hypertension • Diabetes • Hyperlipidaemia • Hyperhomocysteinaemia • Blood coagulation disorders • Systemic inflammatory disorders BRVO = branch retinal vein occlusion. 1. Royal College of Ophthalmologists. Retinal Vein Occlusion Guidelines, July 2015. August 2016 UKEYL08160072 20 BRVO is considered to be the result of compression of a vein at an arteriovenous crossing • The following features of arteriovenous crossings contribute to the risk of venous occlusion: – Artery and vein share a common adventitial sheath1 – The artery lies anterior to the affected vein in 99% of eyes with BRVO2 • More than half of BRVO cases occur in the superotemporal quadrant3 Arteriole Bulge Compression Venule A Narrowing V BRVO = branch retinal vein occlusion. 1. Rehak J, Rehak M. Curr Eye Res. 2008;33:111–131; 2. Zhao J, et al. Ophthalmology. 1993;100:423–428; 3. Klein R, et al. Arch Ophthalmol. 2008;126:513–518. August 2016 UKEYL08160072 21 Thrombus formation also plays a role in the pathogenesis of BRVO BRVO = branch retinal vein occlusion. 1. Browning DJ. Pathophysiology of retinal vein occlusions. In: Retinal Vein Occlusions. New York: Springer Science+Business Media; 2012. August 2016 UKEYL08160072 22 Hypothesised pathogenesis of BRVO1–3 Compression at an AV crossing Degenerative changes of vessel wall Abnormal haematological factors cytokine production4 VEGF PlGF PDGF sICAM-1 MCP-1 IL-6, 8, 12, 13 RVO Stasis Pressure Intraretinal haemorrhage Macular oedema Permeability Ischaemia/ hypoxia Neovascularisation AV = arteriovenous; BRVO = branch retinal vein occlusion; IL = interleukin; MCP = monocyte Vitreous haemorrhage chemotactic protein; PDGF = platelet-derived growth factor; PlGF = placental growth factor; sICAM-1 = soluble intercellular adhesion molecule; VEGF = vascular endothelial growth factor. 1. Karia N. Clin Ophthalmol. 2010;4:809–816; 2. Rehak J, Rehak M. Curr Eye Res. 2008;33:111–131; 3. Browning DJ. August 2016 UKEYL08160072 Pathophysiology of retinal vein occlusions. In: Retinal Vein Occlusions. New York: Springer Science+Business Media; 2012; 23 4. Noma H, et al. Invest Ophthalmol Vis Sci. 2014;55:3878–3885. Pathophysiology: Summary • BRVO is considered to be the result of mechanical narrowing of a branch retinal vein lumen at an arteriovenous crossing • Thrombus formation, as a result of Virchow’s triad, causes venous occlusion – Resulting occlusion leads to increased intraluminal pressure, retinal ischaemia, upregulation of inflammatory cytokines (including VEGF), vascular permeability and angiogenesis • The resulting haemorrhage, neovascularisation, and macular oedema may all lead to vision loss, the main symptom in BRVO August 2016 UKEYL08160072 BRVO = branch retinal vein occlusion; VEGF = vascular endothelial growth factor. 24 Natural history and clinical signs of BRVO August 2016 UKEYL08160072 August 2016 UKEYL08160072 25 BVOS provides information about the natural history of BRVO • BVOS set out to answer three questions on the effectiveness of laser photocoagulation in BRVO1,2 Can scatter laser photocoagulation prevent development of neovascularisation secondary to BRVO? 1 2 3 Can scatter laser photocoagulation prevent vitreous haemorrhage following retinal neovascularisation? Can macular grid laser photocoagulation improve VA in eyes with severe vision degradation due to macular oedema secondary to BRVO? BRVO = branch retinal vein occlusion; BVOS = Branch Vein Occlusion Study; VA = visual acuity. 1. Branch Vein Occlusion Study Group. Am J Ophthalmol. 1984;98:271–282; 2. Branch Vein Occlusion Study Group. Arch Ophthalmol. 1986;104:34–41. August 2016 UKEYL08160072 26 Natural history of BRVO from BVOS Fellow eye involvement1 94–95% of patients present with unilateral BRVO 10% of patients have fellow eye involvement over time Complications2 22% of patients develop neovascularisation without treatment 61% of patients with neovascularisation develop vitreous haemorrhage without treatment Visual outcome3 Without treatment With laser treatment % patients with VA ≥20/40 at 3 years 34% 60% % patients with VA ≤20/200 at 3 years 23% 12% 20/70* 20/40–20/50 Average VA at 3 years *p<0.0001 versus with treatment. 1. Royal College of Ophthalmologists. Retinal Vein Occlusion Guidelines, July 2015; 2. Branch Vein Occlusion Study Group. Arch Ophthalmol. 1986;104:34–41; 3. Branch Vein Occlusion Study Group. Am J Ophthalmol. 1984;98:271–282. August 2016 UKEYL08160072 27 Clinical appearance of BRVO with fundus photography Colour fundus photograph of long-standing BRVO Image courtesy of Peter Addison. BRVO = branch retinal vein occlusion. August 2016 UKEYL08160072 28 Clinical appearance of BRVO with OCT OCT of infero-temporal BRVO with secondary cystoid macular oedema Image courtesy of Louise Downey. BRVO = branch retinal vein occlusion; OCT = optical coherence tomography. August 2016 UKEYL08160072 29 Clinical appearance of BRVO with FA Early frame FA of long-standing BRVO Images courtesy of Peter Addison. BRVO = branch retinal vein occlusion; FA = fluorescein angiography. Late frame FA of long-standing BRVO August 2016 UKEYL08160072 30 Signs of early-stage BRVO: Intraretinal haemorrhage • Intraretinal haemorrhages are generally characteristic of early-stage BRVO1 – Wedge-shaped distribution, with haemorrhage apex at occlusion site1,2 – Confined to one retinal quadrant; distribution determined by occlusion site1 Colour fundus photograph showing intraretinal haemorrhage (blue area) and cotton wool spots (yellow arrows) Image courtesy of Sanjiv Banerjee. BRVO = branch retinal vein occlusion. 1. Yuan A, et al. In: Ryan S, Schachat A, Wilkinson C, et al, eds. Retina. Philadelphia, PA: Elsevier; 2013:1029–1338; 2. Optometry Today. Management & Investigation of Vascular Conditions. Module 13 Part 6: Clinical optometry. August 2016 UKEYL08160072 31 Signs of early-stage BRVO: Blot haemorrhage Colour fundus photograph of BRVO with blot haemorrhage (blue area) August 2016 UKEYL08160072 Image courtesy of Ben Burton. 32 Signs of early-stage BRVO: Dilated, tortuous veins • Main clinical sign of BRVO • Vein appears dilated before (upstream of) the occlusion, and threadlike after (downstream of) the occlusion1 Colour fundus showing a dilated tortuous vein (blue arrow) downstream from the occlusion (yellow arrow) Image courtesy of Robin Hamilton. BRVO = branch retinal vein occlusion. 1. Browning DJ. In: Retinal Vein Occlusions. New York: Springer; 2012. August 2016 UKEYL08160072 33 Collateral blood vessels form in long-standing BRVO1 • Compensatory blood vessels open up in long-standing BRVO1 – Bypass the occlusion, diverting blood to a non-occluded vessel – Seen as a positive development • Differ from vessels formed as a result of neovascularisation:1 – Originate from capillaries and join obstructed and non-obstructed vessels – Do not usually leak on FA • Development appears to be independent of VEGF,2 hence anti-VEGF therapy is unlikely to impede their development FFA showing ghost vessels (yellow arrow) and retinal collaterals (blue arrow) in BRVO Image courtesy of Ben Burton. BRVO = branch retinal vein occlusion; FFA = fundus fluorescein angiography; VEGF = vascular endothelial growth factor. 1. Henkind P. Aust J Ophthalmol. 1981;9:273–277; 2. Montero-Moreno JA, et al. Austin J Clin Ophthalmol. 2014;1(6):4. August 2016 UKEYL08160072 34 Complication of BRVO: Neovascularisation • Neovascularisation is the development of fragile new vessels, prone to haemorrhage1,2 – Generally develop in ischaemic BRVO only3 – Can occur years after onset3 FFA showing disc neovascularisation (yellow arrow) and ischaemia (blue arrow) Image courtesy of Ben Burton. BRVO = branch retinal vein occlusion; FFA = fundus fluorescein angiography. 1. Shilling JS, et al. Br J Ophthalmol. 1976;60:810; 2. Henkind P. Aus J Ophthalmol. 1981;9:273–277; 3. Hayreh SS, et al. Ophthalmology. 1983;90:488–506. August 2016 UKEYL08160072 35 Complication of BRVO: Vitreous haemorrhage • Bleeding into the vitreous is a late-stage complication of BRVO, which often occurs secondary to neovascularisation1 Colour fundus photograph showing mild vitreous haemorrhage from neovascularisation in superotemporal BRVO Image courtesy of Yit Yang. BRVO = branch retinal vein occlusion. 1. Hayreh SS. Indian J Ophthalmol. 1994;42:109–132. August 2016 UKEYL08160072 36 Long-standing BRVO Occlusion point Neovascularisation Colour fundus photograph and FFA of long-standing BRVO Image courtesy of Peter Addison. BRVO = branch retinal vein occlusion; FFA = fundus fluorescein angiography. August 2016 UKEYL08160072 37 Long-standing BRVO Collateral vessels Vascular leakage Colour fundus photograph and FFA of long-standing BRVO Image courtesy of Peter Addison. BRVO = branch retinal vein occlusion; FFA = fundus fluorescein angiography. August 2016 UKEYL08160072 38 Long-standing BRVO Neovascularisation Venous sheathing Collateral vessels Neovascularisation Colour fundus photograph and FFA of long-standing BRVO Image courtesy of Peter Addison. BRVO = branch retinal vein occlusion; FFA = fundus fluorescein angiography. August 2016 UKEYL08160072 39 Natural history and clinical signs: Summary • Intraretinal haemorrhage, blot haemorrhage and macular oedema are signs of early-stage BRVO • Neovascularisation is a complication of BRVO and can lead to vitreous haemorrhage • Collateral vessels often open up in long-standing BRVO to compensate for the occlusion August 2016 UKEYL08160072 BRVO = branch retinal vein occlusion. 40 Initial management of BRVO August 2016 UKEYL08160072 August 2016 UKEYL08160072 41 Diagnosis of BRVO1 • Medical history • Ocular investigations – BCVA – IOP • Diagnostic imaging – Colour fundus photographs – Optical coherence tomography – Fundus fluorescein angiography • Differential diagnosis BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion; IOP = intraocular pressure. 1. Royal College of Ophthalmologists. Retinal Vein Occlusion Guidelines, July 2015. August 2016 UKEYL08160072 42 Patients presenting with BRVO should receive tests to investigate the presence of underlying systemic pathology1 Important tests to perform Additional tests Blood pressure Erythrocyte sedimentation rate Fasting lipid test Full blood count Serum glucose BRVO = branch retinal vein occlusion. 1. Royal College of Ophthalmologists. Retinal Vein Occlusion Guidelines, July 2015. August 2016 UKEYL08160072 43 Management of macular oedema August 2016 UKEYL08160072 August 2016 UKEYL08160072 44 Milestones in the medical treatment of macular oedema secondary to BRVO* Laser Photocoagulation 1977 Intravitreal corticosteroids 1986 2004 BVOS1 Intravitreal anti-VEGF 2007 2009 SCORE2 2010 2011 2012 2013 2014 GENEVA3 BRAVO4 2015 2016 VIBRANT7 HORIZON5 RETAIN6 Treatment first used Trial data first published *Timeline excludes bevacizumab studies. BRVO = branch retinal vein occlusion. 1. Branch Vein Occlusion Study Group. Arch Ophthalmol. 1986;104:34–41; 2. Scott IU, et al. Arch Ophthalmol. 2009;127(9):1115–1128; 3. Haller JA, et al. Ophthalmology. 2010;117:1134–1146; 4. Campochiaro PA, et al. Ophthalmology. 2010;117:1102–1112.e1; 5. Heier JS, et al. Ophthalmology. 2012;119:802–809; 6. Campochiaro PA, et al. Ophthalmology. 2014;121:209–219; 7. Campochiaro PA, et al. Ophthalmology. 2015;122(3):538–544. August 2016 UKEYL08160072 45 Macular grid laser photocoagulation August 2016 UKEYL08160072 August 2016 UKEYL08160072 46 Macular grid laser photocoagulation for BRVO Mechanism • • Improves tight junctions in the retinal pigment epithelium1 Efficacy demonstrated in the Branch Vein Occlusion Study2 Technique • • • Applied in a grid across the macula, avoiding the fovea • 50–100 µm spot size; 20–100 applications3 Guided by fluorescein angigraphy2 Avoid areas of intraretinal haemorrhage2 Side effects • • Scarring4 Loss of central vision4 FFS showing laser scars (arrow) arising from laser photocoagulation Image courtesy of Ben Burton. BRVO = branch retinal vein occlusion; FFA = fundus fluorescein angiography. 1. Stefansson E. Eur Ophthal Rev. 2009;2:76–79; 2. Branch Vein Occlusion Study Group. Am J Ophthalmol. 1984;98:271–282; 3. Royal College of Ophthalmologists. Retinal Vein Occlusion Guidelines, July 2015; 4. Dowler J. J R Soc Med. 2003;96:277–279. August 2016 UKEYL08160072 47 Cumulative proportion of eyes gaining ≥2 lines on two consecutive visits, % BVOS: Significant improvement in VA with grid laser photocoagulation in patients with macular oedema1 Treated Control Follow-up, years August 2016 UKEYL08160072 1. Branch Vein Occlusion Study Group. Am J Ophthalmol. 1984;98:271–282. 48 Intravitreal corticosteroids August 2016 UKEYL08160072 August 2016 UKEYL08160072 49 Intravitreal corticosteroids for BRVO Mechanism Postulated to be downregulation of cytokine expression (including VEGF) to inhibit vascular permeability1 Side effects Important side effects include increased intraocular pressure and cataract formation2,3 Fluocinolone acetonide (not approved for use in BRVO) Triamcinolone acetonide (not currently approved for use in BRVO) Intravitreal dexamethasone implant (approved in the UK for the treatment of macular oedema secondary to BRVO and CRVO) BRVO = branch retinal vein occlusion; CRVO = central retinal vein occlusion; VEGF = vascular endothelial growth factor. 1. Coscas G, et al. Ophthalmologica. 2011;226:4–28; 2. Scott IU, et al. Arch Ophthalmol. 2009;127:1115–1128; 3. Haller JA, et al. Ophthalmology. 2011;118:2453–2460. August 2016 UKEYL08160072 50 Triamcinolone acetonide August 2016 UKEYL08160072 August 2016 UKEYL08160072 51 Note • Triamcinolone is not licensed for the management of macular oedema secondary to BRVO August 2016 UKEYL08160072 52 SCORE-BRVO: Study design N = 411 36-month multicentre, randomised clinical trial comparing intravitreal triamcinolone with grid laser photocoagulation for macular oedema secondary to BRVO Triamcinolone every 4 months 1 mg (n = 136) or 4 mg (n = 138) R Grid laser photocoagulation (n = 137) Baseline to month 12 (N = 367) (primary outcome; visual acuity gain ≥15 letters) Continued treatment to month 24 (N = 238) Continued treatment to month 36 (N = 128) NB: Triamcinolone is not approved in the UK for treatment of macular oedema secondary to BRVO. BRVO = branch retinal vein occlusion. 1. Scott IU, et al. Arch Ophthalmol. 2009;127:1115–1128. August 2016 UKEYL08160072 53 SCORE-BRVO: Patients could receive rescue treatment if pre-specified criteria were met • Participants could receive rescue treatment if there was a loss from baseline in BCVA of ≥15 letters that was present at two consecutive visits Initial treatment Rescue treatment Triamcinolone 4 mg Triamcinolone 4 mg Grid laser photocoagulation Grid laser photocoagulation NB: Triamcinolone is not approved in the UK for treatment of macular oedema secondary to BRVO. BCVA = best-corrected visual acuity. 1. Scott IU, et al. Arch Ophthalmol. 2009;127:1115–1128. August 2016 UKEYL08160072 54 SCORE-BRVO: Inclusion and exclusion criteria Inclusion criteria • • • • Best-corrected ETDRS visual acuity letter score of ≤73 (approximate Snellen equivalent, 20/40 or worse) and ≥19 (approximate Snellen equivalent, 20/400 or better) Centre-involved macular oedema secondary to BRVO present on clinical examination Mean CST of 2 OCT* fast macular scans ≥250 μm Media clarity, pupillary dilation, and subject cooperation sufficient for adequate fundus photographs Exclusion criteria • • • • • • • • • Macular oedema not caused by BRVO Ocular condition where VA would not improve from oedema resolution of the oedema (e.g., foveal atrophy) Cataract reducing VA by ≥3 lines Treatment with intravitreal corticosteroids, or peribulbar steroid injection within 6 months of randomisation History of recent focal/grid macular photocoagulation, panretinal photocoagulation, or anticipated need for panretinal photocoagulation Prior pars plana vitrectomy Major actual/anticipated ocular surgery (incl. cataracts) IOP ≥25 mmHg, open-angle glaucoma, or steroid-induced IOP elevation that required IOP-lowering treatment or pseudoexfoliation Aphakia *OCT2 or Stratus OCT. BRVO = branch retinal vein occlusion; CST = central subfield thickness; ETDRS = Early Treatment Diabetic Retinopathy Study; IOP = intraocular pressure; OCT = optical coherence tomography; VA = visual acuity. 1. Scott IU, et al. Arch Ophthalmol. 2009;127:1115–1128. August 2016 UKEYL08160072 55 SCORE-BRVO: Baseline characteristics were similar between the treatment groups Macular grid laser photocoagulation (n = 137) Triamcinolone acetonide 1 mg (n = 136) Triamcinolone acetonide 4 mg (n = 138) Demographic characteristics Mean (SD) age, years Age range Female, n (%) White, n (%) 66.9 (11.5) 22–90 71 (52) 124 (91) 67.2 (11.5) 32–91 68 (50) 115 (85) 68.1 (10.6) 33–94 63 (46) 123 (89) Study eye characteristics ETDRS letter score, mean (SD) 73–59 (20/40–20/63), n (%) 58–49 (20/80–20/100), n (%) 48–19 (20/125–20/400), n (%) 56.8 (13.0) 70 (51) 34 (25) 33 (24) 58.2 (11.3) 74 (54) 35 (26) 27 (20) 56.1 (13.4) 71 (51) 33 (24) 34 (25) Mean duration of macular oedema (SD) <3 months, n (%) 3–6 months, n (%) 7–12 months, n (%) >12 months, n (%) 4.5 (4.2) 49 (36) 62 (45) 17 (12) 9 (7) 4.1 (3.4) 52 (38) 63 (46) 18 (13) 3 (2) 4.6 (3.9) 51 (37) 60 (43) 22 (16) 5 (4) IOP (mmHg), mean (SD) IOP-lowering medication, n (%) Phakic, n (%) 15.2 (3.1) 6 (4) 115 (84) 15.0 (2.8) 4 (3) 110 (81) 15.1 (3.1) 3 (2) 110 (80) Characteristic NB: Triamcinolone is not approved in the UK for treatment of macular oedema secondary to BRVO. BRVO = branch retinal vein occlusion; ETDRS = Early Treatment Diabetic Retinopathy Study; IOP = intraocular pressure; SD = standard deviation. 1. Scott IU, et al. Arch Ophthalmol. 2009;127:1115–1128. August 2016 UKEYL08160072 56 SCORE-BRVO: Baseline characteristics were similar between the treatment groups (contd.) Characteristic Other clinical characteristics, n (%) Diabetes mellitus Hypertension Coronary artery disease History of cancer Imaging data OCT centre point thickness (μm), mean (SD) Total macular volume (mm3), mean (SD) Area of retinal thickening within the grid (DA) Area of retinal haemorrhage (DA), mean (SD) Area of fluorescein haemorrhage (DA), mean (SD) >5 DA of capillary ischaemia in the eye, n (%) Non-study eye ETDRS letter score, mean (SD) Macular grid laser photocoagulation (n = 137) Triamcinolone acetonide 1 mg (n = 136) Triamcinolone acetonide 4 mg (n = 138) 18 (13) 99 (72) 20 (15) 24 (18) 17 (13) 93 (68) 27 (20) 24 (18) 24 (17) 95 (69) 28 (20) 30 (22) 537 (198) 521 (198) 516 (160) 9.6 (1.8) 10.0 (2.1) 9.5 (1.6) 7.4 (2.7) 7.8 (3.0) 7.4 (2.8) 3.2 (2.5) 2.8 (2.3) 2.9 (2.4) 6.2 (2.4) 6.2 (2.3) 6.0 (2.5) 12 (13) 17 (18) 12 (12) 81.9 (13.2) 83.7 (8.6) 81.9 (10.7) NB: Triamcinolone is not approved in the UK for treatment of macular oedema secondary to BRVO. BRVO = branch retinal vein occlusion; DA = disc area; ETDRS = Early Treatment Diabetic Retinopathy Study; OCT = optical coherence tomography; SD = standard deviation. 1. Scott IU, et al. Arch Ophthalmol. 2009;127:1115–1128. August 2016 UKEYL08160072 57 Proportion of patients gaining ≥15 letters at 12 months (%) SCORE-BRVO: Triamcinolone offers similar benefit to grid laser1 Proportion of patients gaining ≥15 letters (primary outcome) Macular grid laser Triamcinolone photocoagulation acetonide 1 mg (n = 121) (n = 121) Mean no. treatments to month 12 No. patients receiving rescue treatment Triamcinolone acetonide 4 mg (n = 125) 1.5 2.2 2.1 4 7 3 NB: Triamcinolone is not approved in the UK for treatment of macular oedema secondary to BRVO. BRVO = branch retinal vein occlusion; ETDRS = Early Treatment Diabetic Retinopathy Study. 1. Scott IU, et al. Arch Ophthalmol. 2009;127:1115–1128. Mean gain from baseline in ETDRS letters was 4.2, 5.7 and 4.0 letters, for macular grid laser photocoagulation, triamcinolone acetonide 1 mg and triamcinolone acetonide 4 mg, respectively (p=0.70) August 2016 UKEYL08160072 58 SCORE-BRVO: Higher adverse event rates with triamcinolone versus grid laser1 Macular grid laser photocoagulation (n = 137) Triamcinolone acetonide 1 mg (n = 136) Triamcinolone acetonide 4 mg (n = 138) Initiation of IOP-lowering medication* (%) 2 8 41 Lens opacity onset or progression** (%) 13 25 35 Other ocular adverse events (%) 8 4 8 Safety through 12 months NB: Triamcinolone is not approved in the UK for treatment of macular oedema secondary to BRVO. *Standard care vs 1-mg group, p=0.03; standard care vs 4-mg group, p<0.001; and 1-mg vs 4-mg group, p<0.001. **Standard care vs 1-mg group, p=0.03; standard care vs 4-mg group, p<0.001; and 1-mg vs 4-mg group, p=0.10. BRVO = branch retinal vein occlusion; IOP = intraocular pressure. 1. Scott IU, et al. Arch Ophthalmol. 2009;127:1115–1128. August 2016 UKEYL08160072 59 SCORE-BRVO: Summary • Patients were randomised to triamcinolone acetonide 1 mg, triamcinolone acetonide 4 mg, or macular grid laser photocoagulation • Triamcinolone acetonide (1 mg and 4 mg) demonstrated similar efficacy to grid laser for the treatment of macular oedema secondary to BRVO • Triamcinolone acetonide 4 mg was associated with higher rates of adverse events versus triamcinolone acetonide 1 mg and laser NB: Triamcinolone is not approved in the UK for treatment of macular oedema secondary to BRVO. BRVO = branch retinal vein occlusion. August 2016 UKEYL08160072 60 Intravitreal dexamethasone implant August 2016 UKEYL08160072 August 2016 UKEYL08160072 61 Note • The dose and dosing regimen for dexamethasone used in the GENEVA study does not necessarily represent its current recommended posology. Please consult the dexamethasone Summary of Product Characteristics for further details August 2016 UKEYL08160072 62 GENEVA: Study design N = 1267 12-month, phase 3, multicentre, double-masked, trial of treatment with dexamethasone intravitreal implant (DEX) for macular oedema with BRVO or CRVO R DEX implant 0.7 mg† (n = 427) DEX implant 0.35 mg (n = 414) Sham (n = 426) Single DEX implant or sham injection at Day 0 (masked treatment)1 Open-label treatment to month 122 At day 180, n = 997 †Commercially available dose. NB: The dose and dosing regimen for dexamethasone used in the GENEVA study does not necessarily represent its current recommended posology. DEX = dexamethasone; RVO = retinal vein occlusion. 1. Haller JA, et al. Ophthalmology. 2010;117:1134–1146; 2. Haller JA, et al. Ophthalmology. 2011;118:2453–2460. August 2016 UKEYL08160072 63 GENEVA: Retreatment with DEX 0.7 mg at day 180 if one of the following criteria were met BCVA <84 letters (20/20) Retinal thickness >250 µm in the central 1-mm macular subfield as measured by OCT* Procedure would not put patient at significant risk (Investigator's opinion) *OCT2 or OCT3. BCVA = best-corrected visual acuity; DEX = dexamethasone; OCT = optical coherence tomography. 1. Haller JA, et al. Ophthalmology. 2011;118:2453–2460 August 2016 UKEYL08160072 64 GENEVA: Inclusion and exclusion criteria Inclusion criteria • • • Decreased VA as a result of clinically detectable macular oedema associated with CRVO (6 weeks to 9 months duration) or BRVO (6 weeks to 12 months duration) BCVA 34 to 68 letters (approximately 20/200 and 20/50 Snellen equivalent) CST ≥300 μm by OCT* Exclusion criteria • • • • • • • • Presence of clinically significant epiretinal membrane, active retinal or optic disc neovascularisation Active or history of choroidal neovascularisation Presence of rubeosis iridis Active infection, aphakia or anterior-chamber intraocular lens, clinically significant media opacity, glaucoma or current ocular hypertension requiring >1 medication to control IOP in the study eye, or a history of steroid-induced IOP increase in either eye Diabetic retinopathy in either eye Uncontrolled systemic disease Current/anticipated use of systemic steroids/anticoagulants Any ocular condition in the study eye that would prevent a 15-letter improvement in visual acuity *OCT2 or OCT3. BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion; CRVO = central retinal vein occlusion; CST = central subfield thickness; IOP = intraocular pressure; OCT = optical coherence tomography; VA = visual acuity. 1. Haller JA, et al. Ophthalmology. 2011;118:2453–2460. August 2016 UKEYL08160072 65 GENEVA: Baseline characteristics were similar across the treatment groups DEX implant 0.7 mg† (n = 427) DEX implant 0.35 mg (n = 414) Sham (n = 426) Demographic characteristics Mean (range) age, years Male, n (%) White, n (%) 64.7 (33–90) 217 (50.8) 321 (75.2) 64.9 (31–96) 220 (53.1) 312 (75.4) 63.9 (31–91) 240 (56.3) 318 (74.6) Study eye characteristics ETDRS letter score, mean (SD) 54.3 (9.93) 53.9 (10.41) 54.8 (9.86) 157.6 (19–374) 70 (16.4) 219 (51.3) 93 (21.8) 45 (10.5) 153.0 (49–944) 76 (18.1) 218 (52.7) 89 (21.5) 32 (7.7) 156.1 (19–374) 65 (15.3) 220 (51.6) 99 (23.2) 42 (9.9) 27 (6) 24 (6) 16 (4) Phakic, n (%) 373 (88) 362 (87) 387 (91) Retinal thickness (μm), mean (SD) 562 (188) 555 (204) 539 (186) Characteristic Duration of macular oedema, n (%) Mean duration (range) <90 days 90–179 days 180–269 days ≥270 days IOP-lowering medication, n (%) †Commercially available dose. NB: The dose and dosing regimen for dexamethasone used in the GENEVA study does not necessarily represent its current recommended posology. DEX = dexamethasone; ETDRS = Early Treatment Diabetic Retinopathy Study; IOP = intraocular pressure; SD = standard deviation. 1. Haller JA, et al. Ophthalmology. 2010;117:1134–1146. August 2016 UKEYL08160072 66 GENEVA: Baseline characteristics were similar across the treatment groups DEX implant 0.7 mg† (n = 427) DEX implant 0.35 mg (n = 414) Sham (n = 426) Other clinical characteristics, n (%) Diabetes mellitus Hypertension Coronary artery disease 64 (15) 264 (62) 55 (13) 57 (14) 264 (64) 49 (12) 63 (15) 273 (64) 38 (9) Prior laser photocoagulation, n (%) BRVO CRVO 41 (10) 37 (90) 4 (10) 44 (11) 40 (91) 4 (9) 40 (9) 36 (90) 4 (10) Other procedures for RVO, n (%) Haemodilution Intraocular injection 1 (0.2) 0 1 (0.2) 1 (0.2) 2 (0.5) 1 (0.2) Characteristic †Commercially available dose. NB: The dose and dosing regimen for dexamethasone used in the GENEVA study does not necessarily represent its current recommended posology. BRVO = branch retinal vein occlusion; CRVO = central retinal vein occlusion; DEX = dexamethasone. 1. Haller JA, et al. Ophthalmology. 2010;117:1134–1146. August 2016 UKEYL08160072 67 GENEVA: At day 180, proportion of eyes gaining ≥15 letters from baseline with DEX not significantly different from sham1 Proportion of eyes gaining ≥15 letters (%) Proportion of BRVO patients gaining ≥15 letters at day 180 (primary outcome) Dexamethasone implant 0.7 mg† (n = 291) Dexamethasone implant 0.35 mg (n = 260) Sham (n = 279) Study day †Commercially available dose. NB: The dose and dosing regimen for dexamethasone used in the GENEVA study does not necessarily represent its current recommended posology. *p<0.001; **p=0.006; ***p=0.013 versus sham. DEX = dexamethasone. 1. Haller JA, et al. Ophthalmology. 2010;117:1134–1146. August 2016 UKEYL08160072 68 GENEVA: Improvements in BCVA peak at day 60 with DEX1 Mean change in BCVA in BRVO patients (secondary outcome) Mean change in BCVA from baseline (letters) *p=0.008 versus sham **p<0.001 versus sham Dexamethasone implant 0.7 mg† (n = 291) Dexamethasone implant 0.35 mg (n = 260) Sham (n = 279) Time post-treatment (days) †Commercially available dose. NB: The dose and dosing regimen for dexamethasone used in the GENEVA study does not necessarily represent its current recommended posology. BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion; DEX, dexamethasone. 1. Haller JA, et al. Ophthalmology. 2010;117:1134–1146. August 2016 UKEYL08160072 69 GENEVA: Incidence of ocular AEs is higher in DEX groups versus sham1,2 DEX implant 0.7 mg† (n = 421) DEX implant 0.35 mg (n = 412) Sham (n = 423) P-value versus sham 0.35 mg/0.7 mg 62.9 61.9 42.8 p<0.001 Conjunctival haemorrhage, n (%) 85 (20.2) 72 (17.5) 63 (14.9) NS Eye pain, n (%) 31 (7.4) 17 (4.1) 16 (3.8) P=0.023/NS Conjunctival hyperaemia, n (%) 28 (6.7) 27 (6.6) 20 (4.7) NS Cataract, n (%) 31 (7.3) 17 (4.1) 23 (5.4) NS Maculopathy, n (%) 19 (4.5) 22 (5.3) 23 (5.4) NS 0 p<0.001 Characteristic Ocular AEs, % Increased IOP ≥10 mmHg, % 16% (pooled) • Excluding cataract, the ocular AE profile was similar at day 180 and 3602 • In phakic eyes, cataract formation was observed in more re-treated eyes* (29.8%) than delayed-treatment eyes (10.5%; p<0.001)2 †Commercially available dose. NB: The dose and dosing regimen for dexamethasone used in the GENEVA study does not necessarily represent its current recommended posology. *At day 180, patients could receive DEX implant 0.7 mg if BCVA was <84 letters or retinal thickness was >250 µm. AE = adverse event; BRVO = branch retinal vein occlusion; CRVO = central retinal vein occlusion; DEX = dexamethasone; IOP = intraocular pressure. 1. Haller JA, et al. Ophthalmology. 2010;117:1134–1146; 2. Haller JA, et al. Ophthalmology. 2011;118:2453–2460. August 2016 UKEYL08160072 70 GENEVA: Summary • GENEVA compared DEX intravitreal implant 0.7 mg and 0.35 mg with sham for the treatment of macular oedema secondary to BRVO and CRVO • A significantly greater proportion of BRVO patients gained ≥15 letters with DEX (0.35 mg and 0.7 mg) versus sham at days 30, 60, and 90 – However, this difference was not maintained to day 180 • At day 180, incidence of ocular AEs was higher in BRVO patients in the DEX groups (0.7 mg and 0.35 mg) versus sham • Repeat dosing with DEX increased cataract formation August 2016 UKEYL08160072 AEs = adverse events; DEX = dexamethasone; RVO = retinal vein occlusion. 71 Anti-VEGF therapy August 2016 UKEYL08160072 August 2016 UKEYL08160072 72 Intravitreal anti-VEGF therapies block the actions of VEGF to alleviate symptoms of BRVO Side effects3,4 Mechanism Anti-VEGF therapies when injected into the eye block the actions of VEGF. This reduces vascular leakage and macular oedema and inhibits the growth of the blood vessels located within the eye1,2 Ora serrata Limbus Systemic side effects: • Nasopharyngitis, hypertension Ocular side effects: • Conjunctival haemorrhage, retinal haemorrhage Side effects are rare. The most common side effects are those associated with intravitreal injections Macular oedema Cornea Ciliary body Intravitreal injection of anti-VEGF agents BRVO = branch retinal vein occlusion; VEGF = vascular endothelial growth factor. 1. Rehak J, et al. Curr Eye Res. 2008;33:111–131; 2. Mitry D, et al. Coch Database Syst Rev. 2013;1:CD009510; 3. Heier JS, et al. Ophthalmology. 2012;119:802–809; 4. Campochiaro PA, et al. Ophthalmology. 2015;122(3):538–544. August 2016 UKEYL08160072 73 Intravitreal anti-VEGF treatments for BRVO Aflibercept Bevacizumab Not licensed for intravitreal use Affinity maturation Ranibizumab Two ranibizumab molecules can bind each VEGF dimer Anti-VEGF Structure Size (kDa) Target(s) Systemic half-life Fc portion Aflibercept1,2 Recombinant fusion protein 97–115 VEGF-A and PlGF 5–6 days Yes Ranibizumab3 Antibody fragment 48 VEGF-A Approx. 2 h No Recombinant humanised monoclonal antibody 149 VEGF-A 20 days Yes Bevacizumab4,5 BRVO = branch retinal vein occlusion; PlGF = placental growth factor; VEGF = vascular endothelial growth factor. 1. EYLEA Summary of Product Characteristics; 2. EYLEA Prescribing Information; 3. Lucentis: EPAR Scientific Discussion 2007; 4. Avastin Prescribing Information 2014; 5. Avery RL, et al. Br J Ophthalmol. 2014;98:1636–1641. August 2016 UKEYL08160072 74 Bevacizumab August 2016 UKEYL08160072 August 2016 UKEYL08160072 75 Note • Bevacizumab is not licensed for intraocular use August 2016 UKEYL08160072 76 Bevacizumab is unlicensed in BRVO • There are no large randomised controlled trials for bevacizumab in BRVO Study Study type Number of patients Endpoint Russo, 20091 Prospective, randomised study Bevacizumab: 15 Grid laser: 15 12 months Prager, 20092 Prospective clinical trial Bevacizumab: 21 (eyes) 12 months Moradian, 20113 Prospective, randomised clinical trial Bevacizumab: 42 Sham: 39 12 weeks Leitritz, 20134 Prospective interventional case series Bevacizumab: 23 Grid laser: 21 1 year Hikichi, 20145 Single-arm trial Bevacizumab: 105 2 years BRVO = branch retinal vein occlusion. 1. Russo V. Retina. 2009;29(4):511–515; 2. Prager F. Br J Ophthalmol. 2009;93(4):452–456; 3. Moradian S. Graefes Arch Clin Exp Ophthalmol. 2011;249(2):193–200; 4. Leitritz MA. Br J Ophthalmol. 2013;97(2):215–219; 5. Hikichi T. Br J Ophthalmol. 2014;98(2):195–199. August 2016 UKEYL08160072 77 Ranibizumab August 2016 UKEYL08160072 August 2016 UKEYL08160072 78 Note • The dosing regimen for ranibizumab used in the BRAVOHORIZON-RETAIN studies does not represent its current recommended treatment frequency, which varies according to response. Please consult the ranibizumab Summary of Product Characteristics for further details • The 0.3 mg dose of ranibizumab is not licensed in the UK August 2016 UKEYL08160072 79 Efficacy of ranibizumab in BRVO: The BRAVO-HORIZON-RETAIN studies 0.3 mg monthly (n = 134) Patients with macular oedema secondary to BRVO R 0.5 mg monthly (n = 131) RETAIN3 HORIZON2 BRAVO1 0.3 mg monthly PRN 0.5 mg 3-monthly PRN (n = 103) 0.5 mg monthly PRN 0.5 mg 3-monthly PRN (n = 104) 0.5 mg monthly PRN for 12 months then 3-monthly PRN (n = 34) Sham monthly (n = 132) Baseline 0.5 mg 3-monthly PRN (n = 97) 0.5 mg monthly PRN 6 12 24 36 48 60 Time (months) BRAVO primary outcome* HORIZON primary outcome* RETAIN primary outcome* NB: The dosing regimen for ranibizumab used in the BRAVO-HORIZON-RETAIN studies does not represent its current recommended treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK. *Primary efficacy outcome was mean change in BCVA. BRVO = branch retinal vein occlusion; PRN = pro re nata (as needed); R = randomised. August 2016 UKEYL08160072 1. Campochiaro PA, et al. Ophthalmology. 2010;117:1102–1112.e1; 2. Heier JS, et al. Ophthalmology. 2012;119:802–809; 80 3. Campochiaro PA, et al. Ophthalmology. 2014;121:209–219. BRAVO: Ranibizumab in the treatment of macular oedema secondary to BRVO1 BRAVO Patients with macular oedema secondary to BRVO R 0.3 mg monthly (n = 134) 0.3 mg monthly PRN* 0.5 mg monthly (n = 131) 0.5 mg monthly PRN* Sham monthly (n = 132) 0.5 mg monthly PRN* Baseline 6 Time (months) 12 Primary outcome (Mean change in BCVA from baseline to 6 months) NB: The dosing regimen for ranibizumab used in the BRAVO-HORIZON-RETAIN studies does not represent its current recommended treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK. *Re-treatment was based on BCVA ≤20/40 or mean CST ≥250 µm. BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion; CST = central subfield thickness; PRN = pro re nata (as needed); R = randomised. 1. Campochiaro PA, et al. Ophthalmology. 2010;117:1102–1112.e1. August 2016 UKEYL08160072 81 BRAVO: At month 3, patients became eligible for rescue laser photocoagulation if they met the following criteria Haemorrhages had cleared sufficiently to allow safe application of laser Snellen equivalent BCVA ≤20/40 or mean CST ≥250 µm on OCT Gain of <5 letters in BCVA from or decrease of <50 µm in mean CST in past 3 months BCVA = best-corrected visual acuity; CST = central subfield thickness; OCT = optical coherence tomography. 1. Campochiaro PA, et al. Ophthalmology. 2010;117:1102–1112.e1. August 2016 UKEYL08160072 82 BRAVO: Inclusion and exclusion criteria Inclusion criteria • • • • Age ≥18 years of age Foveal centre-involved macular oedema secondary to BRVO diagnosed within 12 months before study initiation BCVA 20/40 to 20/400 Snellen equivalent using the ETDRS charts (letter score ≤73 to ≥19) Mean CST ≥250 µm from two OCT* measurements Exclusion criteria • • • • • • • • • • Prior episode of RVO Brisk afferent pupillary defect (i.e., obvious and unequivocal) >10-letter improvement in BCVA between screening and day 0 Recent intraocular corticosteroid use in study eye History of radial optic neurotomy or sheathotomy History or presence of wet or dry AMD Recent panretinal scatter photocoagulation or sector laser photocoagulation. Evidence upon examination of any diabetic retinopathy CVA or MI within 3 months before day 0 Recent anti-VEGF treatment in study or fellow eye or systemic anti-VEGF pro-VEGF treatment *Stratus OCT. AMD = age-related macular degeneration; BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion; CVA = cerebrovascular accident; CST = central subfield thickness; ETDRS = Early Treatment Diabetic Retinopathy Study; MI = myocardial infarction; OCT = optical coherence tomography; RVO = retinal vein occlusion; VEGF = vascular endothelial growth factor. 1. Campochiaro PA, et al. Ophthalmology. 2010;117:1102–1112.e1. August 2016 UKEYL08160072 83 BRAVO: Baseline characteristics were similar across the treatment groups Ranibizumab 0.3 mg (n = 134) Ranibizumab 0.5 mg (n = 131) Sham (n = 132) Demographic characteristics Mean (SD) age, years Age range Male, n (%) White, n (%) 66.6 (11.2) 43–90 67 (50.0) 112 (83.6) 67.5 (11.8) 41–91 71 (54.2) 107 (81.7) 65.2 (12.7) 26–89 74 (56.1) 108 (81.8) Study eye characteristics ETDRS letter score, mean (SD) 56.0 (12.1) 53.0 (12.5) 54.7 (12.2) Months since diagnosis, n (%) Mean (range) ≤3 months >3 to ≤6 months >6 to ≤9 months >9 to ≤12 months >12 months 3.6 (0–35) 85 (63.4) 29 (21.6) 9 (6.7) 8 (6.0) 3 (2.2) 3.3 (0–13) 88 (67.2) 20 (15.3) 14 (10.7) 7 (5.3) 2 (1.5) 3.7 (0–16) 85 (64.4) 17 (12.9) 12 (9.1) 16 (12.1) 2 (1.5) IOP (mmHg), mean (SD) IOP-lowering medication, n (%) Phakic, n (%) 15.0 (3.3) 20 (14.9) 103 (85.1) 14.9 (3.3) 16 (12.2) 94 (80.3) 14.8 (3.0) 10 (7.6) 93 (78.8) Characteristic NB: The dosing regimen for ranibizumab used in the BRAVO-HORIZON-RETAIN studies does not represent its current recommended treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK. ETDRS = Early Treatment Diabetic Retinopathy Study; IOP = intraocular pressure; SD = standard deviation. 1. Campochiaro PA, et al. Ophthalmology. 2010;117:1102–1112.e1. August 2016 UKEYL08160072 84 BRAVO: Baseline characteristics were similar across the treatment groups (contd.) Ranibizumab 0.3 mg (n = 134) Ranibizumab 0.5 mg (n = 131) Sham (n = 132) 522.1 (201.9) 551.7 (223.5) 488.0 (192.2) Total macular volume (mm3), mean (SD) 9.6 (1.8) 9.8 (2.2) 9.6 (1.8) Area of retinal haemorrhage (DA), mean (SD) 0.1 (0.1) 0.1 (0.1) 0.1 (0.1) Area of fluorescein leakage within the grid (DA), median (%) 6 7 7 >10 DA of capillary non-perfusion (%) 0 0 0 79.4 (13.7) 81.4 (13.8) 79.8 (17.4) Characteristic Imaging data CFT (μm), mean (SD) Non-study eye ETDRS letter score, mean (SD) NB: The dosing regimen for ranibizumab used in the BRAVO-HORIZON-RETAIN studies does not represent its current recommended treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK. CFT = central foveal thickness; DA = disc areas; ETDRS = Early Treatment Diabetic Retinopathy Study; SD = standard deviation. 1. Campochiaro PA, et al. Ophthalmology. 2010;117:1102–1112.e1. August 2016 UKEYL08160072 85 BRAVO: Ranibizumab rapidly and significantly improves BCVA in BRVO1,2 Mean change in BCVA from baseline (ETDRS letters) Mean change in BCVA (primary outcome) Ranibizumab 0.5 mg (n = 131) Ranibizumab 0.3 mg (n = 134) Sham/ranibizumab 0.5 mg (n = 132) Day 0–Month 5 monthly treatment Day 7 Months 6–11 PRN treatment Time (months) Day 0–Month 5 Months 6–11 0.5 mg 0.3 mg Sham 0.5 mg 0.3 mg Sham Mean no. treatments 5.7 5.7 5.5 2.7 2.8 3.6 % patients receiving rescue laser 21.4 20.1 57.6 23.7 30.6 23.5 NB: The dosing regimen for ranibizumab used in the BRAVO-HORIZON-RETAIN studies does not represent its current recommended treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK. *p<0.0001 versus sham; **p<0.01 versus August 2016 UKEYL08160072 sham/0.5 mg. BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion; PRN = pro re nata (as needed). 86 1. Campochiaro PA, et al. Ophthalmology. 2010;117:1102–1112.e1; 2. Brown DM, et al. Ophthalmology. 2011;118:1594–1602. BRAVO: The majority of patients receiving ranibizumab gained ≥15 letters at month 61 Percentage of patients who gained and lost letters at month 6 Percentage of patients (%) Ranibizumab 0.5 mg (n = 131) Ranibizumab 0.3 mg (n = 134) Sham (n = 132) No change 5–9 letters 10–14 letters Vision gain ≥15 letters 5–9 letters 10–14 letters ≥15 letters Vision loss NB: The dosing regimen for ranibizumab used in the BRAVO-HORIZON-RETAIN studies does not represent its current recommended treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK. 1. Campochiaro PA, et al. Ophthalmology. 2010;117:1102–1112.e1. August 2016 UKEYL08160072 87 BRAVO: Ranibizumab rapidly and significantly reduces CFT from baseline in BRVO1,2 Mean change in CFT (secondary outcome) Mean change in CFT from baseline (μm) Ranibizumab 0.5 mg (n = 131) Ranibizumab 0.3 mg (n = 134) Sham/ranibizumab 0.5 mg (n = 132) * Day 7 Day 0–Month 5 monthly treatment Months 6–11 PRN treatment Time (months) NB: The dosing regimen for ranibizumab used in the BRAVO-HORIZON-RETAIN studies does not represent its current recommended treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK. *p<0.0001; **p<0.05 versus sham. The last observation carried forward method was used to impute missing values. BRVO = branch retinal vein occlusion; CFT = central foveal thickness; PRN = pro re nata (as needed). 1. Campochiaro PA, et al. Ophthalmology. 2010;117:1102–1112.e1; 2. Brown DM, et al. Ophthalmology. 2011;118:1594–1602. August 2016 UKEYL08160072 88 BRAVO: Safety to month 12 Ranibizumab 0.3 mg (n = 134) Ranibizumab 0.5 mg (n = 130) Sham (day 0 to month 6) (n = 131) Sham/ranibizumb 0.5 mg (months 6 to 12) (n = 115) Intraocular inflammation 3 (2.2) 0 4 (3.1) 1 (0.9) Vitreous haemorrhage 7 (5.2) 2 (1.5) 6 (4.6) 1 (0.9) Cataract 6 (4.5) 8 (6.2) 4 (3.1) 3 (2.6) Endophthalmitis 0 1 (0.8) 0 0 Lens damage 0 0 0 0 Iris neovascularization 1 (0.7) 1 (0.8) 3 (2.3) 0 Neovascular glaucoma 0 0 0 0 Rhegmatogenous retinal detachment 1 (0.7) 0 0 0 Retinal tear 1 (0.7) 0 0 0 SAEs potentially related to VEGF inhibition 6 (4.5) 6 (4.6) 1 (0.8) 2 (1.7) APTC ATEs 1 (0.7) 2 (1.5) 1 (0.8) 1 (0.9) 0 0 0 0 Safety Ocular AEs Non-ocular SAEs Death NB: The dosing regimen for ranibizumab used in the BRAVO-HORIZON-RETAIN studies does not represent its current recommended treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK. 1. Brown DM, et al. Ophthalmology. 2011;118:1594–1602. August 2016 UKEYL08160072 89 HORIZON: Extension study evaluating the efficacy and safety of ranibizumab in BRVO1 HORIZON¶ BRAVO Patients with macular oedema secondary to BRVO completing BRAVO R 0.3 mg monthly (n = 134) 0.3 mg monthly PRN† 0.5 mg 3-monthly PRN‡ (n = 103) 0.5 mg monthly (n = 131) 0.5 mg monthly PRN† 0.5 mg 3-monthly PRN‡ (n = 104) Sham monthly (n = 132) 0.5 mg monthly PRN† 0.5 mg 3-monthly PRN‡ (n = 97) Baseline 6 12 24 (n = 304) (n = 205) Time (months) 36* (n = 2) Trial termination NB: The dosing regimen for ranibizumab used in the BRAVO-HORIZON-RETAIN studies does not represent its current recommended treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK. *Primary outcome recorded; †Re-treatment was based on BCVA ≤20/40 or mean CST ≥250 µm; ‡Re-treatment was based on CST ≥250 µm or persistent or recurrent macular oedema deemed to be affecting the patient’s VA (according to the investigator). ¶Rescue macular grid laser photocoagulation could be administered if patients had BCVA ≤20/40 caused by macular oedema. BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion; CST = central subfield thickness; PRN = pro re nata; R = randomised. 1. Heier JS, et al. Ophthalmology. 2012;119:802–809. August 2016 UKEYL08160072 90 HORIZON enrolled patients who completed BRAVO Ranibizumab 0.3 mg/0.5 mg (n = 103) Ranibizumab 0.5 mg (n = 104) Sham/ ranibizumab 0.5 mg (n = 97) 67.7 (11.3) 68.3 (12.3) 66.2 (12.2) Male, n (%) 46 (44.7) 58 (55.8) 54 (55.7) White, n (%) 86 (83.5) 84 (80.8) 82 (84.5) 73.6 (11.7) 72.2 (13.8) 68.1 (15.6) 208.5 (144.9) 187.0 (80.8) 196.7 (107.4) Characteristic Mean (SD) age, years ETDRS letter score, mean (SD) CFT, mean (SD), µm NB: The dosing regimen for ranibizumab used in the BRAVO-HORIZON-RETAIN studies does not represent its current recommended treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK. CFT = central foveal thickness; ETDRS = Early Treatment Diabetic Retinopathy Study; RVO = retinal vein occlusion; SD =standard deviation. 1. Heier JS, et al. Ophthalmology. 2012;119:802–809. August 2016 UKEYL08160072 91 HORIZON: Ranibizumab maintained BCVA improvements achieved in BRAVO Ranibizumab 0.5 mg Mean change in BCVA (primary outcome) Sham/0.5 mg ranibizumab HORIZON BRAVO Mean change in BCVA from BRAVO baseline Ranibizumab 0.3 mg/0.5 mg n = 104 (0.5 mg) n = 73 (0.5 mg) n = 66 (0.3 mg/0.5 mg) n = 66 (sham/0.5 mg) n = 103 (0.3 mg) n = 97 (sham) BRAVO baseline 12 15 21 18 24* Time (months) Mean no. injections at month 24 Patients receiving rescue laser, n (%) 2.1 2.4 2.0 5 (7) 4 (6) 3 (5) NB: The dosing regimen for ranibizumab used in the BRAVO-HORIZON-RETAIN studies does not represent its current recommended treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK. *Due to early termination of the study, HORIZON efficacy analyses (secondary outcomes) were presented for 24 rather than 36 months. BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion. 1. Heier JS, et al. Ophthalmology. 2012;119:802–809. August 2016 UKEYL08160072 92 HORIZON: No new safety events reported with long-term use of ranibizumab in BRVO1 Ranibizumab 0.3/0.5 mg (n = 66) Ranibizumab 0.5/0.5 mg (n = 73) Sham/ ranibizumab 0.5 mg (n = 66) Retinal haemorrhage 24.3 21.2 11.8 Conjunctival haemorrhage 20.4 14.4 15.1 Cataract 9.7 5.8 6.5 15 (14.6) 9 (8.7) 8 (8.6) Nasopharyngitis 6 (5.8) 1 (1.0) 7 (7.5) APTC-defined ATEs, n (%) 1 (1.0) 4 (3.8) 1 (1.1) 0 2 (2.0) 0 Ocular AEs (% patients) Non-ocular AEs, n (%) Hypertension Death, n (%) NB: The dosing regimen for ranibizumab used in the BRAVO-HORIZON-RETAIN studies does not represent its current recommended treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK. Safety analyses included all patients over the entire study duration (up to 24 months). 1. Heier JS, et al. Ophthalmology. 2012;119:802–809. August 2016 UKEYL08160072 93 RETAIN: Further extending evaluation of ranibizumab in BRVO1 BRAVO Patients with macular oedema secondary to BRVO completing HORIZON R HORIZON 0.3 mg monthly (n = 134) 0.3 mg monthly PRN‡ 0.5 mg 3-monthly PRN (n = 103)§ 0.5 mg monthly (n = 131) 0.5 mg monthly PRN‡ 0.5 mg 3-monthly PRN (n = 104)§ Sham monthly (n = 132) 0.5 mg monthly PRN‡ 0.5 mg 3-monthly PRN (n = 97)§ Baseline 6 12 24* (n = 205) Time (months) RETAIN 0.5 mg monthly PRN for 12 months then 3-monthly PRN (n = 34)‖ 36 48† 60 (n = 26) Primary outcome (Mean improvement in BCVA) NB: The dosing regimen for ranibizumab used in the BRAVO-HORIZON-RETAIN studies does not represent its current recommended treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK. *Due to early termination of the study, HORIZON efficacy analyses (secondary outcomes) were presented for 24 months rather than 36 months. †Mean BCVA was recorded for all patients enrolled in the BRAVO trial baseline and every 6 months thereafter through 48 months for all patients enrolled in the RETAIN study. ‡Re-treatment was based on BCVA ≤20/40 or mean CST ≥250 µm. §Re-treatment was based on CST ≥250 µm or persistent or recurrent macular oedema deemed to be affecting the patient’s VA (according to the investigator). ‖9% of BRAVO population; re-treatment was based on intravitreal fluid involving the fovea. BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion; CST = central subfield August 2016 UKEYL08160072 thickness; PRN = pro re nata; R = randomised; VA = visual acuity. 94 1. Campochiaro PA, et al. Ophthalmology. 2014;121:209–219. Patients in RETAIN had similar characteristics at BRAVO baseline to the rest of the BRAVO population • Only 9% of the BRAVO population entered RETAIN RETAIN1 (n = 34) BRAVO2 (n = 397) Mean age, years 63.9 66.4 Mean BCVA, ETDRS letter score 54.0 54.6 Mean CFT, µm 465.9 520.5 Characteristic at BRAVO baseline BCVA = best-corrected visual acuity; CFT = central foveal thickness; ETDRS = Early Treatment Diabetic Retinopathy Study. 1. Campochiaro PA, et al. Ophthalmology. 2014;121:209–219; 2. Campochiaro PA, et al. Ophthalmology. 2010;117: 1102–1112.e1. August 2016 UKEYL08160072 95 RETAIN: For some patients BRVO is a chronic condition, requiring long-term treatment1 BRAVO HORIZON RETAIN D0–M5 M6– M11 M12– M17 M18– M23 M24– M29 M30– M35 M36– M41 M42– M47 n 34 34 34 34 34 33 30 28 Mean number of injections 4.2 3.1 1.3 1.3 1.0 1.1 1.1 0.9 • 50% of BRVO patients did not have resolution of macular oedema (mean follow-up 50.2 months) – These patients required an average of 3 injections during last year of follow-up in RETAIN For all patients enrolled in the RETAIN study, mean BCVA was recorded at BRAVO trial baseline and every 6 months thereafter throughout HORIZON up to the end of RETAIN at 48 months. BCVA = best-corrected visual acuity. 1. Campochiaro PA, et al. Ophthalmology. 2014;121:209–219. August 2016 UKEYL08160072 96 RETAIN: Improvements in BCVA in BRAVO were maintained for patients enrolled in RETAIN1 Mean ETDRS letter score Mean ETDRS letter score (secondary outcome) Mean change 20.1 letters from BRAVO baseline (primary outcome) 34 BRAVO • 34 HORIZON RETAIN BCVA improvement of ≥15 letters was observed in 61.8% of patients in RETAIN Blue arrows indicate time of assessment of primary outcomes (RETAIN: mean improvement in BCVA and patients [%] with oedema resolution). BCVA = best-corrected visual acuity. 1. Campochiaro PA, et al. Ophthalmology. 2014;121:209–219. August 2016 UKEYL08160072 97 BRAVO-HORIZON-RETAIN: Summary • The BRAVO-HORIZON-RETAIN trials aimed to assess the efficacy of ranibizumab for the treatment of macular oedema secondary to BRVO • Ranibizumab rapidly and significantly improved BCVA and CRT versus sham at month 12 – These results were maintained to month 24 • Only 9% of the BRAVO population entered RETAIN – No firm conclusions can be made on the long-term efficacy of ranibizumab • For some patients, BRVO is a chronic condition requiring long-term treatment – 50% of patients still required treatment at mean follow-up 50.3 months • No new safety events occurred with the long-term use of ranibizumab August 2016 UKEYL08160072 98 Aflibercept August 2016 UKEYL08160072 August 2016 UKEYL08160072 99 Note • The dosing regimen of aflibercept used in VIBRANT does not necessarily reflect the licensed posology, please refer to the summary of product characteristics for more details. August 2016 UKEYL08160072 100 VIBRANT trial design1,2 N = 183 52-week double-masked, randomised, active-controlled study to assess the efficacy and safety of intravitreal aflibercept versus laser treatment in patients with macular oedema secondary to BRVO or HRVO R Aflibercept Macular laser photocoagulation Primary outcome Proportion of eyes that gained ≥15 ETDRS letters in BCVA from baseline at week 24 Secondary outcomes Change from baseline in BCVA, CRT and NEI VFQ-25 total scores at week 24 BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion; CRT = central retinal thickness; ETDRS = Early Treatment Diabetic Retinopathy Study; NEI VFQ-25 = National Eye Institute 25-item Visual Function Questionnaire. 1. Campochiaro PA, et al. Ophthalmology. 2015;122:538–544; 2. https://clinicaltrials.gov/ct2/show/NCT01521559. August 2016 UKEYL08160072 101 VIBRANT: Inclusion and exclusion criteria Inclusion criteria • • • Adults ≥ 18 years of age Foveal centre-involved macular oedema secondary to BRVO or HRVO diagnosed within 12 months before the screening visit ETDRS BCVA letter score of 73 to 24 (20/40 to 20/320) in the study eye at screening and at day 1 Exclusion criteria • • • • • • • • • Current bilateral manifestation of BRVO Uncontrolled glaucoma defined as ≥25 mmHg on optimal medical regimen, or previous filtration surgery in either the study eye or the fellow eye Insufficient clearing of macular haemorrhage that would prevent the patient from receiving laser treatment safely on day 1 Uncontrolled diabetes mellitus Previous use of intraocular corticosteroids or antiangiogenic drugs in the study eye Recent use of periocular corticosteroids in the study eye Recent use of intraocular or periocular corticosteroids or anti-angiogenic drugs in the fellow eye Previous administration of systemic anti-angiogenic medications Panretinal scatter photocoagulation, sector laser photocoagulation, or macular grid photocoagulation in the study eye BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion; ETDRS = Early Treatment Diabetic Retinopathy Study. 1. Campochiaro PA, et al. Ophthalmology. 2015;122:538–544; 2. https://clinicaltrials.gov/ct2/show/NCT01521559. August 2016 UKEYL08160072 102 VIBRANT: Scheduled dosing (excluding rescue)1,2* Aflibercept 2q4 Active laser Aflibercept 2q8 Sham laser Sham aflibercept Baseline Primary outcome Secondary outcomes End of study assessments Week Aflibercept Patients with BRVO randomised 1:1 Laser *Rescue dosing schedule detailed on subsequent slides. 2q4 = 2 mg every 4 weeks; 2q8 = 2 mg every 8 weeks; BRVO = branch retinal vein occlusion. 1. Campochiaro PA, et al. Ophthalmology. 2015;122:538–544; 2. Clark WL, et al. Ophthalmology. 2016;123:330–336. August 2016 UKEYL08160072 103 VIBRANT: Patients who met one or more of the eligibility criteria could receive rescue treatment from week 12 • Patients in laser arm: – At weeks 12, 16 and 20 option to receive laser rescue – From week 24, option to receive aflibercept 2 mg rescue (3 x 2q4 followed by 2q8) • Patients in aflibercept arm: >50 μm increase in CRT compared with the lowest previous measurement New or persistent cystic retinal changes, sub-retinal fluid, or persistent diffuse oedema in the central OCT subfield – At week 36, option to receive laser rescue • Masking was maintained up to week 52 using sham injection and sham laser Loss of ≥5 letters compared with the best previous measurement because of BRVO in conjunction with any increase in CRT BRVO = branch retinal vein occlusion; CRT = central retinal thickness; OCT = optical coherence tomography. 1. Campochiaro PA, et al. Ophthalmology. 2015;122:538–544. August 2016 UKEYL08160072 104 VIBRANT is the first phase III anti-VEGF clinical trial to include ischaemic BRVO patients • Definition of ‘ischaemic BRVO’ varies between studies – In VIBRANT: ≥10 disc areas of retinal capillary non-perfusion1 – In BVOS: >5 disc diameters of retinal capillary non-perfusion2 • BRAVO did not include patients with ischaemic BRVO3 – Patients with brisk afferent pupillary defect were excluded BRVO = branch retinal vein occlusion CRVO = central retinal vein occlusion. 1. Campochiaro PA, et al. Ophthalmology. 2015;122:538–544; 2. Branch Vein Occlusion Study Group. Arch Ophthalmol. 1986;104:34–41; 3. Campochiaro PA, et al. Ophthalmology. 2010;117:1102–1112. August 2016 UKEYL08160072 105 VIBRANT: Rescue treatment schedule1,2 Aflibercept 2q4 Active laser Aflibercept 2q8 Sham laser Rescue treatment Sham aflibercept Baseline Primary outcome Secondary outcomes End of study assessments Week Aflibercept Patients with BRVO randomised 1:1 Aflibercept + rescue treatment Laser Laser + rescue treatment Dashed outline represents an opportunity for rescue treatment; †Rescue laser ≥12 weeks apart from the last laser treatment; ‡Subjects in the laser arm eligible for rescue aflibercept treatment starting at week 24, and received three aflibercept 2q4 injections, followed by aflibercept 2q8. 2q4 = 2 mg every 4 weeks; 2q8 = 2 mg every 8 weeks; BRVO = branch retinal vein occlusion. 1. Campochiaro PA, et al. Ophthalmology. 2015;122:538–544. 2. Clark WL, et al. Ophthalmology. 2016;123:330–336. August 2016 UKEYL08160072 106 VIBRANT: Baseline demographics and disease characteristics were balanced between treatment arms1 Laser (n = 90)† Aflibercept (n = 91) 63.9 (11.4) 67.0 (10.4) Women, n (%) 36 (40.0) 47 (51.6) Race [white], n (%) 62 (68.9) 70 (76.9) Mean age, years (SD) BCVA Mean, letters (SD) 57.7 (11.3) 58.6 (11.4) >20/200 (35‒73 letters), n (%) 83 (92.2) 85 (93.4) ≤20/200 (24‒34 letters), n (%) 7 (7.8) 6 (6.6) Perfused* 62 (68.9) 55 (60.4) Non-perfused** 16 (17.8) 20 (22.0) Cannot grade 10 (11.1) 16 (17.6) 2 (2.2) 0 553.5 (188.1) 558.9 (185.9) Mean, days (SD) 43.1 (38.8) 42.4 (43.4) <3 months, n (%) 72 (80.0) 75 (82.4) ≥3 months, n (%) 11 (12.2) 7 (7.7) 7 (7.8) 9 (9.9) Retinal perfusion status, n (%) Missing Mean CRT, μm (SD) Full analysis set. *<10 disc areas of retinal capillary non-perfusion. **≥10 disc areas of retinal capillary non-perfusion. †BCVA data not available for 2/92 randomised patients. BCVA = best-corrected visual acuity; BRVO = branch retinal vein occlusion; CRT = central retinal thickness; SD = standard deviation. Time since BRVO diagnosis Missing, n (%) 1. Campochiaro PA, et al. Ophthalmology. 2015;122:538–544. August 2016 UKEYL08160072 107 VIBRANT: Fewer patients given aflibercept vs laser photocoagulation required rescue treatment1,2 Baseline to week 24 Week 24 to week 52 Baseline to week 52 Aflibercept arm Mean number of aflibercept injections 5.7 Patients receiving rescue laser, n (%) 9.0 9 (10.6) Laser arm Mean number of laser treatments received Mean number of rescue AFL injections received Patients receiving rescue AFL injections, n (%) 1.7 4.4 67 (80.7) August 2016 UKEYL08160072 1. Campochiaro PA, et al. Ophthalmology. 2015;122:538–544; 2. Clark WL, et al. Ophthalmology. 2016;123:330–336. 108 VIBRANT: Significantly more eyes gained ≥15 ETDRS letters with aflibercept vs laser therapy1,2 Proportion of patients who gained ≥15 letters from baseline (%) Proportion of patients gaining ≥15 letters (primary outcome) Laser (n = 90†) Aflibercept 2q4 (n = 91) 0–24 weeks Laser + rescue Aflibercept aflibercept 2q8 (n = 91) (n = 90†) 24–52 weeks Full analysis set. Missing data imputed using the last observation carried forward method.*p=0.0003 versus laser; **p=0.0296 versus laser. 2q4 = 2 mg every 4 weeks; 2q8 = 2 mg every 8 weeks; ETDRS = Early Treatment Diabetic Retinopathy Study. 1. Campochiaro PA, et al. Ophthalmology. 2015;122:538–544; 2. Clark WL, et al. Ophthalmology. 2016;123:330–336. August 2016 UKEYL08160072 109 VIBRANT: Gains in BCVA were rapid and sustained to 52 weeks in eyes treated with aflibercept1,2 Mean change from baseline in BCVA (ETDRS letters) Mean change in BCVA (secondary outcome) Time (weeks) Aflibercept 2q4 (n = 91) Laser (n = 90†) Aflibercept 2q8 (n = 91) Laser + rescue aflibercept (n = 90†) Full analysis set. Missing data imputed using the last observation carried forward method. *p<0.0001; **p=0.0035 versus laser. †BCVA data not available for 2/92 randomised patients. 2q4 = 2 mg every 4 weeks; 2q8 = 2 mg every 8 weeks; BCVA = best-corrected visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study. 1. Campochiaro PA, et al. Ophthalmology. 2015;122:538–544; 2. Clark WL, et al. Ophthalmology. 2016;123:330–336. August 2016 UKEYL08160072 110 VIBRANT: Early treatment is important to maximise outcomes in patients with BRVO1,2 Mean change from baseline in BCVA (ETDRS letters) Mean change in BCVA (secondary outcome) Time (weeks) Aflibercept 2q4 (n = 91) Laser (n = 90†) Aflibercept 2q8 (n = 91) Laser + rescue aflibercept (n = 90†) Full analysis set. Missing data imputed using the last observation carried forward method. *p<0.0001; **p=0.0035 versus laser. †BCVA data not available for 2/92 randomised patients. 2q4 = 2 mg every 4 weeks; 2q8 = 2 mg every 8 weeks; BCVA = best-corrected August 2016 UKEYL08160072 visual acuity; BRVO = branch retinal vein occlusion; ETDRS = Early Treatment Diabetic Retinopathy Study. 111 1. Campochiaro PA, et al. Ophthalmology. 2015;122:538–544; 2. Clark WL, et al. Ophthalmology. 2016;123:330–336. VIBRANT: More patients gained vision and fewer lost vision with aflibercept vs laser at week 241 Proportion of patients gaining/losing vision (secondary outcome) * Aflibercept 2q4 (n = 91) Proportion of patients (%) Laser (n = 90)† * * * * Any vision loss Any vision gain ≥10 letters Full analysis set. Missing data imputed using the last observation carried forward method. *p<0.05 versus laser; †BCVA data not available for 2/92 randomised patients. 2q4 = 2 mg every 4 weeks; BCVA = best-corrected visual acuity. 1. Campochiaro PA, et al. Ophthalmology. 2015;122:538–544. ≥15 letters ≥30 letters August 2016 UKEYL08160072 112 VIBRANT: CRT reductions were rapid and sustained over 52 weeks in eyes treated with aflibercept1,2 Mean change in CRT (secondary outcome) Mean change from baseline in CRT (μm) Time (weeks) Aflibercept 2q4 (n = 91) Laser (n = 90) Aflibercept 2q8 (n = 91) Laser + rescue aflibercept (n = 90) Full analysis set. Missing data imputed using the last observation carried forward method. *p<0.0001; **p=0.0218 versus laser. 2q4 = 2 mg every 4 weeks; 2q8 = 2 mg every 8 weeks; BCVA = best-corrected visual acuity; CRT = central retinal thickness. 1. Campochiaro PA, et al. Ophthalmology. 2015;122:538–544; 2. Clark WL, et al. Ophthalmology. 2016;123:330–336. August 2016 UKEYL08160072 113 VIBRANT: NEI VFQ-25 near and distance activities were improved with aflibercept versus laser Mean change from baseline in subscale score on the NEI VFQ-25 Questionnaire Mean change in NEI VFQ-25 subscale scores (secondary outcome) Aflibercept 2q4 (n = 91) Laser (n = 90) † * ** Near Distance Visual activities activities dependency Week 241 Near Distance Visual activities activities dependency Week 522 *p=0.003, **p=0.0047, †p=0.0061 versus laser. NEI VFQ-25 = National Eye Institute 25-item Visual Function Questionnaire. 1. Campochiaro PA, et al. Ophthalmology. 2015;122:538–544; 2. Clark WL, et al. Ophthalmology. 2016;123:330–336. August 2016 UKEYL08160072 114 VIBRANT: Aflibercept increased the proportion of eyes with retinal capillary perfusion at week 241 Laser (n = 90) • Week 24 Baseline Week 24 Relative difference Baseline Proportion of perfused eyes (%) Proportion of perfused eyes (pre-specified exploratory outcome) Aflibercept 2q4 (n = 91) At 52 weeks, after rescue treatment in the laser arm, the perfusion status was similar in the two arms2 *p=0.0497 versus laser at week 24. 2q4 = 2 mg every 4 weeks. 1. Campochiaro PA, et al. Ophthalmology. 2015;122:538–544; 2. Clark WL, et al. Ophthalmology. 2016;123:330–336. August 2016 UKEYL08160072 115 VIBRANT: Aflibercept increased the proportion of eyes without intraretinal or subretinal fluid1 Proportion of dry eyes (%) Proportion of “dry” eyes (ad hoc exploratory outcome) Absolute difference Absolute difference Baseline Week Week 24 52 Laser + rescue aflibercept (n = 90)† Baseline Week Week 24 52 Aflibercept (n = 91) *p=0.0303 aflibercept versus laser. †Majority of patients in the laser group received aflibercept rescue treatment from week 24. 1. Clark WL, et al. Ophthalmology. 2016;123:330–336. August 2016 UKEYL08160072 116 VIBRANT: Incidence of adverse events from baseline to weeks 24 and 52 was similar for aflibercept vs laser 24 weeks1 52 weeks2 Laser Aflibercept (n = 92) (n = 91) Laser + rescue aflibercept Aflibercept (n = 91) (n = 92) Ocular AEs (study eye), n (%) 25 (27.2) 34 (37.4) 44 (47.8) 45 (49.5) Conjunctival haemorrhage 4 (4.3) 18 (19.8) 14 (15.2) 22 (24.2) Retinal neovascularisation 3 (3.3) 0 4 (4.3) 0 0 1 (1.1) 0 1 (1.1) 46 (50.0) 43 (47.3) 63 (68.5) 61 (67.0) 10 (10.9) 6 (6.6) 15 (16.3) 10 (11.0) 5 (5.4) 6 (6.6) 8 (8.7) 8 (8.8) Non-ocular serious AEs, n (%) 9 (9.8) 8 (8.8) 10 (10.9) 13 (14.3) APTC-defined ATEs*, n (%) 1 (1.1) 0 2 (2.2) 0 Death, n (%) 1 (1.1) 0 1 (1.1) 0 Serious ocular AEs, n (%) Non-ocular AEs, n (%) Hypertension Nasopharyngitis Safety analysis set. *Antiplatelet Trialists' Collaboration (APTC)-defined arterial thromboembolic events (ATEs) include non-fatal stroke, non-fatal myocardial infarction, and vascular death as adjudicated by a masked committee. AE = adverse event. 1. Campochiaro PA, et al. Ophthalmology. 2015;122:538–544; 2. Clark WL, et al. Ophthalmology. 2016;123:330–336. August 2016 UKEYL08160072 117 VIBRANT: Summary • The first Phase III trial to compare an anti-VEGF agent with the prior standard of care (macular grid laser photocoagulation therapy) in BRVO • Patients were randomised to aflibercept 2q4 or laser – At week 24, patients in the aflibercept group were switched to 2q8 regimen • A significantly higher proportion of patients taking aflibercept gained ≥15 ETDRS letters from baseline at week 24 (primary outcome) and at week 52, when compared with patients receiving laser therapy • Mean CRT reductions from baseline to week 24 and week 52 were significantly greater in the aflibercept arm vs laser arm • Aflibercept is well tolerated in the treatment of visual impairment due to macular oedema secondary to BRVO August 2016 UKEYL08160072 118 Posology of aflibercept for RVO (BRVO or CRVO)1 • After the initial injection, treatment is given monthly. The interval between two doses should not be shorter than one month. • If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, Eylea should be discontinued. • Monthly treatment continues until maximum visual acuity is achieved and/or there are no signs of disease activity. Three or more consecutive, monthly injections may be needed. • Treatment may then be continued with a treat-and-extend regimen with gradually increased treatment intervals to maintain stable visual and/or anatomic outcomes, however there are insufficient data to conclude on the length of these intervals. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly. • The monitoring and treatment schedule should be determined by the treating physician based on the individual patient’s response. • Monitoring for disease activity may include clinical examination, functional testing or imaging techniques (e.g. optical coherence tomography or fluorescein angiography). Consecutive monthly dosing until disease stability (≥3 injections) Treat and extend Injection visits Monitoring visits BRVO = branch retinal vein occlusion; CRVO = central retinal vein occlusion. 1. EYLEA SmPC. August 2016 UKEYL08160072 119 Management of macular oedema: Summary • The efficacy of macular grid laser photocoagulation for the treatment of macular oedema secondary to BRVO was demonstrated in BVOS – Mechanism is not fully understood • Intravitreal corticosteroids downregulate cytokine expression to inhibit vascular permeability – Triamcinolone demonstrated similar benefits to grid laser, but was associated with higher rates of adverse events – DEX demonstrated short-term improvements in BCVA, but repeat dosing increased cataract formation • Intravitreal anti-VEGF therapies block the actions of VEGF to alleviate symptoms of BRVO – Both ranibizumab and aflibercept are effective for the treatment of visual impairment caused by macular oedema secondary to BRVO August 2016 UKEYL08160072 DEX = dexamethasone. 120 Management of other complications • Neovascularisation • Vitreous haemorrhage August 2016 UKEYL08160072 August 2016 UKEYL08160072 121 Sector pan-retinal photocoagulation August 2016 UKEYL08160072 August 2016 UKEYL08160072 122 Sector pan-retinal photocoagulation for BRVO What it treats Mechanism • Neovascularisation secondary to BRVO • Reduces risk of vitreous haemorrhage • Standard of care for peripheral retinal ischaemia based on Branch Vein Occlusion Study1,2 • Reduces oxygen demand by destroying photoreceptors within the retina3 • Hypoxia is corrected and production of cytokines is normalised3 Side effects Technique • Laser is directed at quadrant of ischaemia • Avoid areas of intraretinal haemorrhage1 • Scarring4 • Loss of central vision4 A B Inner eye Schematic diagram showing change in retina (A) before and (B) after scatter laser photocoagulation. Destruction of pigment epithelium and photoreceptors occurs Photoreceptors Pigment epithelium Outer eye BRVO = branch retinal vein occlusion; BVOS = Branch Vein Occlusion Study; VEGF = vascular endothelial growth factor. 1. Branch Vein Occlusion Study Group. Am J Ophthalmol. 1984;98:271–282; 2. Branch Vein Occlusion Study Group. Arch Ophthalmol. 1986;104:34–41; 3. Stefansson E. Eur Ophthal Rev. 2009;2:76–79; 4. Dowler J. J R Soc Med. 2003;96:277–279. August 2016 UKEYL08160072 123 BVOS outcomes led to laser photocoagulation becoming standard of care for BRVO • Scatter laser photocoagulation in patients with BRVO:1 – Prevented development of neovascularisation – Prevented vitreous haemorrhage in patients with neovascularisation BRVO = branch retinal vein occlusion; BVOS = Branch Vein Occlusion Study. 1. Branch Vein Occlusion Study Group. Arch Ophthalmol. 1986;104:34–41. August 2016 UKEYL08160072 124 Vitrectomy August 2016 UKEYL08160072 August 2016 UKEYL08160072 125 Vitrectomy for BRVO • Vitrectomy is only necessary in situations where secondary complications are present Bleeding What it treats1 • Vitreous haemorrhage • Tractional retinal detachment (macular involvement) • Epiretinal membrane Light source Retina Vitrector Vitreous humor Pars plana vitrectomy. Figure shows use of a cutting instrument to remove vitreous humor BRVO = branch retinal vein occlusion. 1. Buddi R, et al. Available here: http://www.reviewofophthalmology.com/content/d/wills_resident_case_series/ d/1213/p/22849/c/25432/. Accessed February 17, 2015. August 2016 UKEYL08160072 126 Management of other complications: Summary • Scatter laser photocoagulation is used to treat neovascularisation secondary to BRVO, and to reduce the risk of vitreous haemorrhage • Vitrectomy is only necessary in situations where secondary complications are present – Treats vitreous haemorrhage, tractional retinal detachment, and epiretinal membrane secondary to BRVO August 2016 UKEYL08160072 BRVO = branch retinal vein occlusion; VEGF = vascular endothelial growth factor. 127 RCO guidelines for the management of patients presenting with BRVO Measure VA VA is better than 20/40 no yes Regularly observe progress for 3 months Macular oedema and haemorrhages are NOT masking the macula yes None Measure level of ischaemia on FFA Mild to moderate Consider treatment with anti-VEGF therapy or dexamethasone no After 3 months Anti-VEGF therapy or dexamethasone for three months Severe No treatment. Regularly observe for neovascularisation BRVO = branch retinal vein occlusion; FFA = fundus fluorescein angiography; VA = visual acuity; VEGF = vascular endothelial growth factor. 1. Royal College of Ophthalmologists. Retinal Vein Occlusion Guidelines, July 2015. August 2016 UKEYL08160072 128 Local patient pathway • [Placeholder – please insert information as needed] August 2016 UKEYL08160072 129 NICE guidelines for the management of patients with BRVO • Intravitreal dexamethasone implant: https://www.nice.org.uk/Guidance/TA229 • Ranibizumab: https://www.nice.org.uk/guidance/ta283 • Aflibercept: https://www.nice.org.uk/guidance/indevelopment/gidta10004 August 2016 UKEYL08160072 BRVO = branch retinal vein occlusion. 130 Back-up slides August 2016 UKEYL08160072 August 2016 UKEYL08160072 131 Several growth and inflammatory factors are associated with macular oedema in BRVO1 Median value Factor Relative P value difference Control group BRVO group sVEGFR-1, pg/mL 790 2433 3.08 <0.001 sVEGFR-2, pg/mL 85.5 537 6.28 <0.001 VEGF, pg/mL 22.5 83.5 3.71 0.033 PlGF, pg/mL 0.37 1.69 4.57 0.004 PDGF-AA, pg/mL 15.1 30.3 2.01 <0.001 sICAM-1, ng/mL 0.06 0.29 4.83 0.002 MCP-1, pg/mL 839 1721 2.05 <0.001 IL-6, pg/mL 2.73 8.17 2.99 0.013 IL-8, pg/mL 2.54 21.0 8.27 <0.001 IL-12, pg/mL 0.14 2.48 17.71 0.001 IL-13, pg/mL 0.63 4.09 6.49 0.025 BRVO = branch retinal vein occlusion; IL = interleukin; MCP = monocyte chemotactic protein; PDGF = platelet-derived growth factor; PlGF = placental growth factor; sICAM-1 = soluble intercellular adhesion molecule 1; sVEGFR-1 = soluble vascular endothelial growth factor (VEGF) receptor 1; sVEGFR-2 = soluble vascular endothelial growth factor (VEGF) receptor 2. 1. Noma H, et al. Invest Ophthalmol Vis Sci. 2014;55:3878–3885. August 2016 UKEYL08160072 132 HORIZON: Ranibizumab maintained CFT improvements achieved in BRVO Ranibizumab 0.5 mg Mean change in CFT from BRAVO baseline (μm) Mean change in CFT (secondary outcome) Ranibizumab 0.3 mg/0.5 mg Sham/0.5 mg ranibizumab HORIZON BRAVO n = 96 (sham) n = 103 (0.3 mg) n = 65 (0.3 mg/0.5 mg) n = 63 (sham/0.5 mg) n = 72 (0.5 mg) n = 104 (0.5 mg) BRAVO baseline 12 15 18 21 24* 2.1 2.4 2.0 5 (7) 4 (6) 3 (5) Time (months) Mean no. injections at month 24 Patients receiving rescue laser, n (%) NB: The dosing regimen for ranibizumab used in the BRAVO-HORIZON-RETAIN studies does not represent its current recommended treatment frequency; the 0.3 mg dose of ranibizumab is not licensed in the UK. *Due to early termination of the study, HORIZON August 2016 UKEYL08160072 efficacy analyses (secondary outcomes) were presented for 24 rather than 36 months. CFT = central foveal thickness. 133 1. Heier JS, et al. Ophthalmology. 2012;119:802–809. RETAIN: Improvements in CFT in BRAVO were maintained for patients enrolled in RETAIN Mean change in CFT (secondary outcome) • 50% of BRVO patients in RETAIN had resolution of macular oedema • Those without resolution had three injections during the last year of follow-up Dark grey line represents a value of 172 mm, the mean CFT reported in normal patients. Blue arrows indicate time of assessment of primary outcomes (RETAIN: mean improvement in BCVA and patients [%] with oedema resolution). BRVO = branch retinal vein occlusion; CFT = central foveal thickness. 1. Campochiaro PA, et al. Ophthalmology. 2014;121:209–219. August 2016 UKEYL08160072 134 Anti-VEGF therapy and ischaemia1 • VIBRANT is the first phase III anti-VEGF clinical trial to include ischaemic BRVO patients – Defined as ≥10 disc areas of retinal capillary non-perfusion – Aflibercept may be effective at reducing retinal ischaemia Further investigation is needed Proportion of eyes with a decrease in retinal ischaemia from baseline Laser/rescue aflibercept Aflibercept Week 24, % 17.6 29.0 Week 52, % 29.6 34.7 August 2016 UKEYL08160072 1. Clark WL, et al. Ophthalmology. 2016;123:330–336. 135 BVOS study design1,2 Group I N = 319 Group II N = 82 Scatter laser photocoagulation Control Scatter laser photocoagulation Control Group III N = 139 Grid laser photocoagulation Control BVOS = Branch Vein Occlusion Study. 1. Branch Vein Occlusion Study Group. Am J Ophthalmol. 1984;98:271–282; 2. Branch Vein Occlusion Study Group. Arch Ophthalmol. 1986;104:34–41. August 2016 UKEYL08160072 136 BVOS: Inclusion criteria1,2 Group I • • • • • BRVO occurring 3–18 months earlier An area of 5 disc diameters of retinal involvement Sufficient clearing of intraretinal haemorrhage to permit safe laser photocoagulation No diabetic retinopathy Absence of other ocular disease-threatening VA Group II • • • • • BRVO occurring 3–18 months earlier Disc and/or peripheral neovascularisation documented by stereo colour fundus photography, and Sufficient clearing of intraretinal haemorrhage to permit safe laser photocoagulation No diabetic retinopathy Absence of other ocular disease-threatening VA Group III • • • • • • BRVO occurring 3–18 months earlier Macular oedema reducing VA to 20/40 or worse Fluorescein angiographic evidence of macular oedema involving the fovea Sufficient clearing of intraretinal haemorrhage to permit safe laser photocoagulation Absence of haemorrhage in the fovea Absence of other ocular disease-threatening VA BRVO = branch retinal vein occlusion; BVOS = Branch Vein Occlusion Study; VA = visual acuity. 1. Branch Vein Occlusion Study Group. Am J Ophthalmol. 1984;98:271–282; 2. Branch Vein Occlusion Study Group. Arch Ophthalmol. 1986;104:34–41. August 2016 UKEYL08160072 137 Sheathotomy during vitrectomy for BRVO What it treats Only treatment available that treats the cause of the occlusion1 Mechanism Separates common sheath connecting artery and vein at arteriovenous crossing1 Arteriovenous adventitial sheathotomy. A sharp tool is used to separate the common adventitial sheath of the artery and vein • High-risk procedure that may not provide additional benefits1–3 BRVO = branch retinal vein occlusion. 1. Osterloh MD, Charles S. Arch Ophthalmol. 1988;106:1469–1471; 2. Kumagai K, et al. Retina. 2007;27:49–54; 3. Charbonnel J, et al. Graefes Arch Clin Exp Ophthalmol. 2004;242:223–228. August 2016 UKEYL08160072 138 Prescribing information (1) Eylea® 40 mg/ml solution for injection in a vial (aflibercept) Prescribing Information (Refer to full Summary of Product Characteristics (SmPC) before prescribing) Presentation: 1 ml solution for injection contains 40 mg aflibercept. Each vial contains 100 microlitres, equivalent to 4 mg aflibercept. Indication(s): Treatment of neovascular (wet) age-related macular degeneration (AMD), macular oedema secondary to retinal vein occlusion (branch RVO or central RVO), visual impairment due to diabetic macular oedema (DMO) in adults and visual impairment due to myopic choroidal neovascularisation (myopic CNV). Posology & method of administration: For intravitreal injection only. Must be administered according to medical standards and applicable guidelines by a qualified physician experienced in administering intravitreal injections. Each vial should only be used for the treatment of a single eye. The vial contains more than the recommended dose of 2 mg. The extractable volume of the vial (100 microlitres) is not to be used in total. The excess volume should be expelled before injecting. Refer to SmPC for full details. Adults: The recommended dose is 2 mg aflibercept, equivalent to 50 microlitres. For wAMD treatment is initiated with one injection per month for three consecutive doses, followed by one injection every two months. No requirement for monitoring between injections. After the first 12 months of treatment, and based on visual and/or anatomic outcomes, the treatment interval may be extended such as with a treat-and-extend dosing regimen, where the treatment intervals are gradually increased to maintain stable visual and/or anatomic outcomes; however there are insufficient data to conclude on the length of these intervals. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly. The schedule for monitoring should therefore be determined by treating physician and may be more frequent than the schedule of injections. For RVO (branch RVO or central RVO), after the initial injection, treatment is given monthly at intervals not shorter than one month. Discontinue if visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment. Treat monthly until maximum visual acuity and/or no signs of disease activity. Three or more consecutive, monthly injections may be needed. Treatment may then be continued with a treat and extend regimen with gradually increased treatment intervals to maintain stable visual and/or anatomic outcomes, however there are insufficient data to conclude on the length of these intervals. Shorten treatment intervals if visual and/or anatomic outcomes deteriorate. The monitoring and treatment schedule should be determined by the treating physician based on the individual patient’s response. For DMO, initiate treatment with one injection/month for 5 consecutive doses, followed by one injection every two months. No requirement for monitoring between injections. After the first 12 months of treatment, and based on visual and/or anatomic outcomes, the treatment interval may be extended such as with a treat-and-extend dosing regimen, where the treatment intervals are gradually increased to maintain stable visual and/or anatomic outcomes; however there are insufficient data to conclude on the length of these intervals. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly. The schedule for monitoring should therefore be determined by the treating physician and may be more frequent than the schedule of injections. If visual and anatomic outcomes indicate that the patient is not benefiting from continued treatment, treatment should be discontinued. For myopic CNV, a single injection is to be administered. Additional doses may be administered if visual and/or anatomic outcomes indicate that the disease persists. Recurrences should be treated as a new manifestation of the disease. The schedule for monitoring should be determined by the treating physician. The interval between two doses should not be shorter than one month. Hepatic and/or renal impairment: No specific studies have been conducted. Available data do not suggest a need for a dose adjustment. Elderly population: No special considerations are needed. Limited experience in those with DMO over 75 years old. Paediatric population: No data available. Contraindications: Hypersensitivity to active substance or any excipient; active or suspected ocular or periocular infection; active severe intraocular inflammation. Warnings & precautions: As with other intravitreal therapies endophthalmitis has been reported. Aseptic injection technique essential. Patients should be monitored during the week following the injection to permit early treatment if an infection occurs. Patients must report any symptoms of endophthalmitis without delay. Increases in intraocular pressure have been seen within 60 minutes of intravitreal injection; special precaution is needed in patients with poorly controlled glaucoma (do not inject while the intraocular pressure is ≥ 30 mmHg). Immediately after injection, monitor intraocular pressure and perfusion of optic nerve head and manage appropriately. There is a potential for immunogenicity as with other therapeutic proteins; patients should report any signs or symptoms of intraocular inflammation e.g pain, photophobia or redness, which may be a clinical sign of hypersensitivity. Systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events have been reported following intravitreal injection of VEGF inhibitors. Safety and efficacy of concurrent use in both eyes have not been systemically studied. No data is available on concomitant use of Eylea with other antiVEGF medicinal products (systemic or ocular). Caution in patients with risk factors for development of retinal pigment epithelial tears including large and/or high pigment epithelial retinal detachment. Withhold treatment in patients with: rhegmatogenous retinal detachment or stage 3 or 4 macular holes; with retinal break and do not resume treatment until the break is adequately repaired. August 2016 UKEYL08160072 139 Prescribing information (2) Withhold treatment and do not resume before next scheduled treatment if there is: decrease in best-corrected visual acuity of ≥30 letters compared with the last assessment; central foveal subretinal haemorrhage, or haemorrhage ≥50%, of total lesion area. Do not treat in the 28 days prior to or following performed or planned intraocular surgery. Eylea should not be used in pregnancy unless the potential benefit outweighs the potential risk to the foetus. Women of childbearing potential have to use effective contraception during treatment and for at least 3 months after the last intravitreal injection. Populations with limited data: There is limited experience of treatment with Eylea in patients with ischaemic, chronic RVO. In patients presenting with clinical signs of irreversible ischaemic visual function loss, aflibercept treatment is not recommended. There is limited experience in DMO due to type I diabetes or in diabetic patients with an HbA1c over 12% or with proliferative diabetic retinopathy. Eylea has not been studied in patients with active systemic infections, concurrent eye conditions such as retinal detachment or macular hole, or in diabetic patients with uncontrolled hypertension. This lack of information should be considered when treating such patients. In myopic CNV there is no experience with Eylea in the treatment of non-Asian patients, patients who have previously undergone treatment for myopic CNV, and patients with extrafoveal lesions. Interactions: No available data. Fertility, pregnancy & lactation: Not recommended during pregnancy unless potential benefit outweighs potential risk to the foetus. No data available in pregnant women. Studies in animals have shown embryo-foetal toxicity. Women of childbearing potential have to use effective contraception during treatment and for at least 3 months after the last injection. Not recommended during breastfeeding. Excretion in human milk: unknown. Male and female fertility impairment seen in animal studies with high systemic exposure not expected after ocular administration with very low systemic exposure. Effects on ability to drive and use machines: Possible temporary visual disturbances. Patients should not drive or use machines if vision inadequate. Undesirable effects: Very common: Visual acuity reduced, conjunctival haemorrhage (phase III studies: increased incidence in patients receiving anti-thrombotic agents), eye pain. Common: retinal pigment epithelial tear, detachment of the retinal pigment epithelium, retinal degeneration, vitreous haemorrhage, cataract (nuclear or subcapsular), corneal abrasion or erosion, increased intraocular pressure, blurred vision, vitreous floaters, vitreous detachment, injection site pain, foreign body sensation in eyes, increased lacrimation, eyelid oedema, injection site haemorrhage, punctate keratitis, conjunctival or ocular hyperaemia. Serious: cf. CI/W&P - in addition: blindness, endophthalmitis, cataract traumatic, transient increased intraocular pressure, vitreous detachment, retinal detachment or tear, hypersensitivity (during the post-marketing period, reports of hypersensitivity included rash, pruritus, urticaria, and isolated cases of severe anaphylactic/anaphylactoid reactions), vitreous haemorrhage, cortical cataract, lenticular opacities, corneal epithelium defect/erosion, vitritis, uveitis, iritis, iridocyclitis, anterior chamber flare, arterial thromboembolic events (ATEs) are adverse events potentially related to systemic VEGF inhibition. There is a theoretical risk of arterial thromboembolic events, including stroke and myocardial infarction, following intravitreal use of VEGF inhibitors. Consult the SmPC in relation to other side effects. Overdose: Monitor intraocular pressure and treat if required. Incompatibilities: Do not mix with other medicinal products. Special Precautions for Storage: Store in a refrigerator (2°C to 8°C). Do not freeze. Unopened vials may be kept at room temperature (below 25°C) for up to 24 hours before use. Legal Category: POM. Package Quantities & Basic NHS Costs: Single vial pack £816.00. MA Number(s): EU/1/12/797/002. Further information available from: Bayer plc, Bayer House, Strawberry Hill, Newbury, Berkshire RG14 1JA, United Kingdom. Telephone: 01635 563000. Date of preparation: September 2016 Eylea® is a trademark of the Bayer Group Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Bayer plc. Tel.: 01635 563500, Fax.: 01635 563703, Email: [email protected] August 2016 UKEYL08160072 140