Steroids and DME Scott E. Pautler, M.D. Associate Clinical Professor of Ophthalmology University of South Florida Tampa, FL

Case Presentation 71 year old woman with type 2 diabetes for 12 years with gradually decreasing vision OU Visual acuity: R-20/50, L-20/125 Slit lamp: 2+ nuclear sclerosis IOP 18 OU Fundus: DME OU; moderate NPDR OU

Top: Red-Free: moderate NPDR with exudates Bottom: FA shows significance leakage OS > OD

3/23/2009 OCT shows center-involved macular edema OU OS shows large cyst that may indicate tissue loss 3/23/2009

Right Eye Left Eye Treatments: Focal – 2 IVK – 10 CE/IOL Treatments: VTX/ILM peel PRP -2 Over a five-year period of treatment, both eyes required focal laser and IVK OS > OD Both eyes required CE IOL OS also required PRP and Vtx/peel ILM indicating more severe DR Note the spikes in the graph showing CSMT response to injection therapy

For your interest I show many perspectives of OCT at the last visit. On the bottom image the right eye has very little residual edema and the left eye eye show persistent edema at this time point 2/5/2014

Visual Acuity and OCT Outcomes Date Eye CSMT (µ) VA 3/23/2009 Right 398 20/50 Left 397 20/125 2/5/2014 267 20/20 490 20/100 Functionally: Over the 5 years of treatment, the right eye improved from 20/50 to 20/20 The left eye marginally improved from 20/125 to 20/100

Steroid Mechanism of Action Decrease VEGF production Widespread anti-inflammatory effects More rapid onset and more profound initial effect on edema than anti-VEGF agents Adverse effects: cataract, glaucoma Read slide Induction of lipcortin which reduce potent inflammatory mediators (prostaglandins and leukotrienes) Sonodo 2011 ref for onset of effect. Pre-injection IVTA 1 month later

Steroid Agents Let’s review the variety of steroid preparations that are available in the US Missing from this photo is Iluvien, which will be discussed as well

Triamcinolone vs Focal/Grid Laser DRCR Protocol B: 840 eyes Three-year results Problems: 79% of eyes were phakic and IVTA dosing interval was ≥ 4 months Treatment Mean BCVA gains Δ CSMT In microns Cataract Surgery Glaucoma Surgery Glaucoma Drops Focal/Grid +5 letters -158 3% IVTA 1 mg 0 letters -103 46% 2% IVTA 4 mg -114 83% 4 (1.6%) 12% DRCR.net Protocol B compared IVTA with Focal laser IVTA superior to laser at 4 months, Equal at 12 months, inferior at 2-3 years. 79% of all eyes were phakic at the start. 64% attrition by 3yrs; IVTA =>4month intervals (inappropriate dosing hampered comparison). Dose-related complications of cataract and glaucoma were evident rendering IVTA 1mg superior to 4mg

Combination IVTA + Focal/Grid Laser (FGL) DRCR Protocol I: Pseudophakic eyes (206) Two-year results Treatment Mean Δ BCVA (letters) Δ CSMT (μ) IVTA 4 mg + FGL +8 -128 Sham + FGL +5 -145 IVR + Prompt FGL -126 IVR + Deferred FGL +9 -148 Note: At one year follow-up, IVTA and IVR groups were equal in reducing edema when both groups were seen at monthly intervals. After first year, IVTA group was only seen every 4 months Suboptimal timing of IVTA may account for inferior ability to thin the macula with IVTA

Triamcinolone Options FDA approved Crystal Size Dissolution Profile Cost Pseudo Endophth Preserved No 18.86 μ Faster $9.32 ≤7% Preservative- Free Yes 11.51 μ Slower $157.58 ≤1% In the US there are two preparations to choose from when using IVTA: Preserved (Kenalo) and Non-preserved (Triesence); FDA approval; crystal size favors Kenalog for duration of action But Chen etal reported slower dissolution profile of Triesence. There is not agreement in literature on which preparation lasts the longest. Cost; Pseudoendophthalmitis occurs more frequently with Kenalog, but can be mitigated by decanting in my experience.

Dexamethasone Implant Recently approved by FDA for DME Bio-erodible Duration ≤6 months Ozurdex MEAD Study Group 2014: 1048 eyes; 20/50-20/200; CRT ≥300μ; 3-year Dexamtethasone was recently approved by FDA for use for DME Bioerodable; 3-6 month duration MEAD study: PRP was allowed, but NOT Focal laser. 42% attrition by 3 years Review numbers; RED is Ozurdex Treatment ≥15 letter improvement Mean CRT (μ) Cataract Glaucoma Surgery Sham injection 12% -42 20% 0% Dex 0.35 mg 18.4% -108 64% 0.3% Dex 0.70 mg 22.2% -112 68% 0.6%

Dexamethasone Implant BEVORDEX Study (AAO subspecialty meeting) 1-year result of RCT bevacizumab vs dexamethasone Dexamethasone superior functional and anatomic outcomes in pseudophakic eyes Mean number of injections: 3.7 Dexamethasone injections 8.6 bevacizumab injections Gillies

Fluocinolone Implant Recently approved by FDA for DME Non-responders; Duration ≤3 years FAME Study 2012: 953 eyes; failed FLT; 20/50-20/400; CRT ≥250μ; 3-year study Treatment ≥15 letter improvement Mean CRT (μ) Cataract Glaucoma Surgery Sham injection* 21% NG 51% 0.5% Fluo 0.2 μg/d 33% 82% 4.8% Fluo 0.5 μg/d 32% 89% 8.1% Iluvien was very recently approved by FDA for DME in non-steroid responders Iluvien implant supplies slow, continuous release of Fluo for up to three years, but is NON-bioerodible. 75% required only one injection In the FAME study, significant improvement was seen in Va and CRT with 75% of eyes requiring only one implant injection. RED preparation is Iluvien implant; Note dose dependent effect on cataract and glaucoma {Rescue injections (IVTA, IVA, IVL): Sham 33%, Fljuo 0.2 15%, Fluo 0.5 16%}; 30% attrition *Rescue treatment with focal laser and/or anti-VEGF occurred more often in Sham

Steroids and IOP Risk Factors: Glaucoma, OHT, steroid response, young age, higher loading dose Steroid Agent (values adjusted by control group) ≥10mm over baseline ≥25mm at any exam Any IOP meds Surgery For Attrition by 3 years Triamcinolone 1 mg 18% (14%) - 2% (0%) 0% (0%) 64% 4 mg 33% (29%) 12% (9%) 4% (4%) Dexamethasone Impl 0.70 mg 28% (24%) 32% (28%) 42% (33%) 1% (1%) 42% Fluocinolone Impl 0.19 mg 34% (24%) 20% (16%) 38% (24%) 5% (4%) 30% Cataract may be expected with steroid use, but it is readily treatable. Glaucoma, on the other hand, is a chronic disease that threatens permanent blindness. We do not have level 1 evidence-based comparison among the steroid agents to speak definitively on the relative risks of IOP-related problems Risk factors are know: see list In an effort to compare IOP-related adverse effects, I compiled the cumulative incidence of comparable end-points from the available RCT studies. THEN, in an effort to reduce the confounding effect of different populations groups among the studies, I elected subtract the incidence of events by the respective incidence in the sham groups (give example) Left column: the agents Second column: IOP 10mm or greater over baseline- show dose response with triamcinolone, but no major difference among groups otherwise Third column: IOP 25mm or great at any exam- Oz>Iluvien BUT note in col 4 shows greater use of IOP meds in Oz>Iluvien compared with greater use of surgery in Iluvien>Oz groups in last column When comparing IVTA with Oz and Iluvien, the lower IOP events may relate to under-dosing of IVTA as described earlier CONCLUSION: there is currently no reliable evidence that one agent is safer than another regarding IOP events based on current evidence

Case Selection Pseudophakic, Non-Glaucoma/Suspect Eyes AC IOL: consider avoiding an implant Post vitrectomy: consider avoiding IVTA (storm) Prior glaucoma surgery offers limited protection against steroid-IOP response

Case Selection DME resistant to anti-VEGF/laser* Macula-threatening exudates (BEVORDEX) One-time use for DME prior to surgery: PRP laser cataract surgery *FAME October 2014 Ophthalmology * Fluocinolone implant relatively more effective in chronic edema (>3yrs)

Steroid Selection Triamcinolone Steroid implant Less expensive (Kenalog®) More frequent injection Greater peak/trough effect Steroid implant More expensive Fewer injections Better pharmacokinetics (Iluvien®>Ozurdex®)

Thank you Scott E. Pautler, M.D. Tampa, FL