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

2. 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

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

4. 3/23/2009 OCT shows center-involved macular edema OU
OS shows large cyst that may indicate tissue loss
3/23/2009

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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.

13. 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%

14. 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

15. 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 %, Fluo %}; 30% attrition
*Rescue treatment with focal laser and/or anti-VEGF occurred more often in Sham

16. 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

17. 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

18. 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)

19. 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®)

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