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NW2007 Intravitreal Avastin Injection for Diabetic Retinopathy
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NW2007 Intravitreal Avastin Injection for Diabetic Retinopathy

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  • 1. Intravitreal Injections for Diabetic Retinopathy Nawat Watanachai VR Fellow SCGH
  • 2. What to inject into the vitreous of diabetic eyes? QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. Corticosteroid Anti-Vascular endothelial growth factors (anti-VEGF) Avastin (Bevacizumab) Lucentis (Ranibizumab) Macugen(Pegaptanib)
  • 3. In which eyes? I. II. Diabetic macular edema Adjunctive therapy PDR with NV that not response to laser PDR with cataract/ VH, unable to add laser III. Eyes with active NV and/or VH, planned for Vx
  • 4. DR Leakage/ occlusion of small vessels Wide spread of ischemic retina Imbalance between PG/IL/pro-angiogenic factor VEGF & anti-angiogenic factor PEDF, Angiostatin VEGF-A + other factors  NV
  • 5. Corticosteroids − ↓ extravasation from leaking blood vessels (inhibit archidonic pathway that produce IL/PG) − ↓ proliferation of fibroblasts and granulation tissue − ↓ breakdown of the blood-retinal barrier − ↓ production of vascular endothelial growth factor (VEGF)
  • 6. AntiVEGF : Targeting VEGF pathway
  • 7. Anti-VEGF antiVEGF Structure Target Vitreous (wk) Macugen (Pegaptanib) RNA aptamer VEGF165 isoform 6 Lucentis Fab portion All VEGF-A (Ranibizumab) isoforms 4-8 Avastin (Bevacizumab) 8-12 Full-length Ab All VEGF-A isoforms
  • 8. In which eyes? I. Diabetic macular edema II. Adjunctive therapy PDR with NV that not response to laser PDR with VH, unable to add laser Eyes with active NV and/or VH, planned for Vx
  • 9. Diabetic Macula Edema - ETDRS - Repeated macular laser for focal/diffuse DME may do more damage to the vision - Diffuse DME is much less responsive to laser than focal DME
  • 10. I. DME: Intravitreal Triamcinolone (IVTA) Intravitreal triamcinolone acetonide for diabetic macular edema: A prospective randomized study. Jonas JB et al. J Ocul Pharmacol Ther. 2006; 22. Unilateral 20 mg IVTA injection in bilateral DME. 33 cases VA improvement by 3 lines: 39% in the IVTA (20mg) eyes vs. 0% in the control eyes at 6 months. Big dose Effect lasts approximately 7-8 mths IIOP ~52%
  • 11. I. DME : Avastin - persistent DME - Intravitreal Avastin therapy for persistent diffuse diabetic macular edema - Christos Haritoglou et al, Retina 2006;26. - 51 patients with diffuse CSME (age 23-79 yrs) - Persistent DME after any treatment (beyond 6 mths period) - Laser 18 eyes/ IVTA 17 eyes/ - Avastin 1.25 mg/0.05 ml - 6 wks follow up Vitrectomy 6 eyes
  • 12. I. DME : Avastin - persistent DME baseline 6 wks 12 wks VA (ETDRS letters) 25.88+/14.43 31.32+/27.05+/14.33 14.83 (P=0.001) (not sig) CRT (Microns) 501+/-163 416+/-180 377+/-117 (P=0.001) (P=0.001) -Intravitreal Avastin therapy for persistent diffuse diabetic macular edema. -Christos Haritoglou et al, Retina 2006;26.
  • 13. I. DME : Avastin - persistent DME - 15 eyes (29%) increased in VA of at least 3 lines - 70% received a second injection at 12 wks - Factors influencing treatment success - Baseline VA +++ - Macular ischemia --- CRT + - Age, previous treatment, area of peripheral ischemia +/-Intravitreal Avastin therapy for persistent diffuse diabetic macular edema. -Christos Haritoglou et al, Retina 2006;26.
  • 14. I. DME : Avastin - primary Rx Primary intravitreal Avastin for DME , Results from the Pan-American Collaborative Retina Study Group at 6-mth follow up. J.Arevalo et al. Ophthalmology 2007 April, 114(4). 6 centers from 6 contries 110 diffuse DME eyes/ 88 pts Mean age 59.7+/-9.3 yrs 1.25 mg of Avastin injection Follow up 6.31 mths (6-9)
  • 15. I. DME : Avastin - primary Rx VA Baseline 6/48 or 0.87 logMAR Final 6/24 or 0.6 logMAR (P<0.0001) Improved >/= 2 snellen lines 43 eyes (55.1%) Stable 32 eyes (41.1%) Decreased >/= 2 snellen lines 3 eyes (3.8%) Mean CRT Baseline 387.0 +/- 182.8 microns Final 275.7 +/- 108.3 microns (P<0.0001) 16 eyes(20.5%) needed 2nd injection Primary intravitreal Avastin for DME. J.Arevalo et al. Ophthalmology 2007 April, 114(4).
  • 16. I. I. DME : Lucentis - VEGF is a critical stimulus for DME, - Nguyen QD et al. Am J Ophthalmol. 2006 Dec; 142(6). - 10 pts with chronic DME - Lucentis 0.5 mg at 0, 1, 2 ,4 ,6 mth
  • 17. I. DME : Lucentis mean VA Mean CRT baseline 20/80 503 7 mth 20/40 P=0.005 257 P=0.005 VA improved in all 10 pts CRT decreased in all 10 pts VEGF is a critical stimulus for DME, Nguyen QD et al. Am J Ophthalmol. 2006 Dec; 142(6).
  • 18. I. DME : Macugen A Phase II randomized double-masked trial of pegaptanib an anti-VEGF aptamer, for DME; The Macugen Diabetic Retinopathy Study Group; Ophthalmology 2006; 113:23. Eyes with CSME involving the center of macula corresponding leakage from FA 172 subjects, VA 20/50-20/320 Inject 0.3/1/ 3mg q 6 wks for 12-30 wks (3-6 injections)
  • 19. I. DME : Macugen Result at 36 wk, 0.3 mg Median VA 20/50 vs 20/63 (P=0.04) Gain VA>10 letters 34% vs 10% (P=0.003) Gain VA>15 letters 18% vs 7 % (P=0.12) Mean decrease thickness 68 vs -4 microns Decrease thickness>100 microns 42% vs 6% (P=0.02) Need laser 25% VS 48% (P=0.04) result at 82 wks (1 yr after last possible injection) Decrease thickness 122 vs 49 microns Required less frequency of laser treatment 1 endophthalmitis from 652 injections A Phase II randomized double-masked trial of pegaptanib an anti-VEGF aptamer, for DME; The Macugen Diabetic Retinopathy Study Group; Ophthalmology 2006; 113:23
  • 20. DME - Focal DME with microaneurysms --> focal laser - Diffuse DME which do not response to grid laser --> IVTA or antiVEGF - DME with vitreous traction --> PPV/ combination
  • 21. DME : diffuse type - Predicting factors - Younger age - Lower degree of maculr ischemia - Better pre-injection VA - Shorter duration of ME - Thicker CRT
  • 22. In which eyes? I. II. III. Diabetic macular edema Adjunctive therapy PDR with NV that not response to laser PDR with cataract/VH/etc, unable to add laser Eyes with active NV and/or VH, planned for Vx
  • 23. II. Adjunctive treatment for PDR : Avastin -Intravitreal avastin for persistent new vessels in DR (IBEPE Study) -Rodrigo Jorge et al. RETINA 2006;26. -15 eyes with actively leaking NV refractory to PRP and BCVA worse than 20/40. -age 60.08 +/- 7.75 yrs (49–73 yrs). -1.5 mg of Avastin
  • 24. persistent active NV 5½ months after PRP 1 week 6 weeks 12 weeks II. Adjunctive treatment for PD R : Avastin
  • 25. II. Adjunctive treatment for PDR : Avastin baseline 6 wk 1 wk 12 wk
  • 26. II. Adjunctive treatment for PDR : Avastin baseline 6 wk 1 wk 12 wk
  • 27. II. Adjunctive treatment for PDR : Avastin Baseline 1 wk 6wk 12wk Mean NV leakage area (mm2) 27.79+/- 5.43 +/6.29 2.18 5.65 +/- 5.50+/1.76 1.24 VA 20/160 20/125 P=.05 20/125 P=.05 20/125 P=.05 IOP (mmHg) 14.93 +/- 15.33 +/- 15.20 15.26 0.77 0.84 +/- 0.78 +/-0.81 Recurrence of NV observed in 14/15 eyes at wk12
  • 28. II. Adjunctive treatment for PDR : Macugen Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic ind ividuals. Macugen Diabetic Retinopathy Group. Ophthalmology 2006;113:23–28. Regression of ocular neovascularization occurred in 8/13 (62%) of patients in the peg aptanib treatment group at 36 weeks. 3/8 NV progressed at wk52 after cessation of Macugen at wk30 0/3 in sham group
  • 29. II. Adjunctive treatment for PDR : Macugen
  • 30. In which eyes? I. II. Diabetic macular edema Adjunctive therapy PDR with NV that not response to laser PDR with VH, unable to add laser III. Eyes with active NV and/or VH, planned for Vx
  • 31. III. Eyes with active NV and/or VH, planned for Vx : Avastin Intravitreal Avastin : An Adjunctive Therapy for Proliferative Diabetic Vitrectomy C. Saovaprut et al,Thai J Ophthalmol 2006; 20(1) intravitreal bevacizumab 1 mg/0.04 ml. Vitrectomy in 1-4 weeks after injection. Intraoperative homeostasis, postoperative bleeding and retinal reattachment were observed.
  • 32. CASE 1 : Avastin VA 6/400 VA of 20/200, 12 wks after injection. C. Saovaprut et al,Thai J Ophthalmol 2006; 20(1):20-26.
  • 33. CASE 2 : Avastin Preoperative intravitreal injection of Avastin Postoperative at 1 week C. Saovaprut et al,Thai J Ophthalmol 2006; 20(1):20-26.
  • 34. CASE 3 : Avastin C. Saovaprut et al,Thai J Ophthalmol 2006; 20(1):20-26.
  • 35. III. Eyes with active NV and/or VH, planned for Vx : Avastin -result 30 eyes in 28 patients The regression of NV was noted as early as 2448 hours and completed at average 1 week. Significantly less intraoperative bleeding, intraocular diathermy was used only 4 times in 30 surgeries No immediately or late postoperative bleeding and anatomical retinal reattachment in all patients at last follow-up. (1-10 months; mean 5.6 months). C. Saovaprut et al,Thai J Ophthalmol 2006; 20(1):20-26.
  • 36. In which eyes? I. II. Diabetic macular edema Adjunctive therapy PDR with NV that not response to laser PDR with cataract/ VH, unable to add laser III. Eyes with active NV and/or VH, planned for Vx
  • 37. Adverse effects : IVTA Infectious/ non infectious endophthalmitis 1:1000 Glaucoma, transient IIOP 25-50% of cases Need glaucoma surgery 1-2% RD in eyes with previously treated RB Cataract 50-90% in 2 yrs esp PSC Significant cataract that need surgery 15-20% in 1 yr Reported : MH, persistent unsealed scleral wound(30G)
  • 38. Adverse effects : IVTA Glaucoma/ OHT Start ~1wk after injection Risk factors Younger age Pre-op IOP > 16 mmHG Repeated injection Pre-op glaucoma
  • 39. Adverse Effects : Anti-VEGF Foreign body sensation Subconjunctival hemorrhage Transient IIOP/ pain/ floaters Uveitis (esp Lucentis) Worsening of preexisting PRH RPE tear Endophthalmitis Allergic reaction Others eg. MI, hypertension
  • 40. Ongoing Studies A phase 2 evaluation of anti-VEGF therapy for DME : Avastin/ US NIH (laser/ avastin/ avastin+laser) READ2 study : avastin+laser VS Lucentis+laser for DME Multicenter randomised clinical trial of laser treatment plus IVTA for DME (Phase III, AUS, 2005-2008) Macugen compared to sham injection in patients with DME involving the center of the macula (Phase III,2005-2010) Efficacy study of Lucentis in the treatment of DME Laser-Lucentis-triamcinolone for PDR Laser-Lucentis-triamcinolone for DME RESOLVE : safety and efficacy of avastin in DME with center involvement Intravitreal avastin vs photocoagulation for PDR Intravitreal avastin for treatment of NVG Effect of macugen on surgical outcomes and VEGF levels in diavetic patients with PDR or CSME Study for the treatment of iris NV with Macugen (2006-2007) Macugen to prevent worsening of macular edema following cataract surgery in diabetic Lucentis VS Avastin for DME/ US NIH