Effective Treatment Strategies for Center-Involved DME with Good Visual Acuity

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Discover the latest treatment protocols for center-involved diabetic macular edema (DME) in eyes with good visual acuity, including the role of anti-VEGF agents, laser therapy, and observation. Explore findings from clinical trials and understand how to optimize care for patients with DME to maintain optimal visual outcomes.

  • DME treatment
  • Visual acuity
  • Anti-VEGF therapy
  • Laser therapy
  • Clinical trials
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  1. DRCR Retina Network Treatment for Center-Involved DME in Eyes with Good Visual Acuity (Protocol V) 1

  2. Financial Disclosures Funding/Support: Cooperative Agreement with NEI and NIDDK of NIH, U.S. Department of Health and Human Services. Additional Contributions: Regeneron provided the aflibercept for the study. In addition, Regeneron provided funds to the DRCR Retina Network to defray the study s clinical-site costs. 2

  3. Anti-VEGF Has Not Been Evaluated In Eyes That Have Center-Involved DME with Good VA (20/25 Or Better) How should we treat eyes with center-involved DME and visual acuity 20/25 or better? 3

  4. Treatment of DME in ETDRS ETDRS Focal/Grid Laser Eyes with CI-DME and VA 20/25 or better at baseline ETDRS Observation ~40% of eyes in ETDRS with CI-DME had good VA. N = 120 N = 251 Visual acuity decrease by 5 letters (one line) at 2 years 27% 40% 4

  5. Eyes in Protocol I and ETDRS with 5 Letter VA Loss 45 ETDRS Observation Only (20/25 or better) ETDRS Laser Group (20/25 or better) DRCR.net I Ranibizumab+deferred laser (20/32) 40 N = 110 35 30 N = 113 N = 118 25 N = 231 % of Eyes N = 237 20 N = 246 15 10 N = 28 N = 26 N = 28 5 0 0 4 8 12 18 20 24 Months 5

  6. Anti-VEGF Has Not Been Evaluated In Eyes That Have Center-Involved DME with Good VA (20/25 Or Better) How should we treat eyes with center- involved DME and visual acuity 20/25 or better? Anti-VEGF? Focal/Grid Laser (Add Anti-VEGF if VA drops)? Observation (Add anti-VEGF if VA drops)? 6

  7. Study Design Randomized Multicenter Clinical Trial (N = 91 Sites) Outcomes 18 years old with type 1 or type 2 diabetes Center-involved DME on OCT* VA letter score 20/25 or better* No or minimal** prior treatment for DME Aflibercept Primary Proportion of eyes that lost 5 letters of VA at 2 years Laser+ (Aflibercept prn) Secondary Mean change in VA and CST from baseline at 1 and 2 years Observation+ (Aflibercept prn) *Confirmed at 2 visits 1-28 days apart (screening and randomization) **No more than 1 laser and/or 4 injections, at least 12 months ago 7

  8. Randomization 702 eyes of 702 participants total Initiation With Included in the Primary Analyses 104 Weeks N = 205 (94%)* Aflibercept N = 226 N = 226 Laser+ (Aflibercept prn) Observation+ (Aflibercept prn) N = 212 (91%)* N = 240 N = 240 N = 208 (90%)* N = 236 N = 236 *Excluding deaths 8

  9. Study Follow-up Outcome Visit Schedule Treatment Visit Schedule Initiation With Visits q 4 weeks during the first 24 weeks, q 4-16 weeks thereafter. Aflibercept All participants had visits at 1 and 2 years for outcome assessment. Laser+ (Aflibercept prn) Visits at 8 and 16 weeks followed by q 16-week visits thereafter. If VA/OCT worsen or aflibercept is initiated, visits at q 4, 8, or 16 weeks depending on disease progression and treatment. Observation+ (Aflibercept prn) 9

  10. Study Treatment Initiation With Injection at baseline Evaluation at each visit for re-injection based on protocol criteria Aflibercept Focal/grid laser at baseline Evaluation at each visit for initiating aflibercept based on VA loss* Retreatment with laser if protocol criteria are met Laser+ (Aflibercept prn) Observation+ (Aflibercept prn) No treatment at baseline Evaluation at each visit for initiating aflibercept based on VA loss* * VA decrease 10 letters at 1 visit or 5-9 letters at two consecutive visits 10

  11. Participant Baseline Characteristics Initiation With Laser N = 240 60 34% 92% 7.6 67% 15% 15% 4% Aflibercept N = 226 59 42% 93% 7.6 64% 16% 14% 6% Observation N = 236 60 37% 89% 7.6 68% 17% 11% 4% Age (y), median Female Type 2 Diabetes HbA1c (%), median Race/Ethnicity Other White Black/African American Hispanic or Latino 11

  12. Ocular Baseline Characteristics Initiation With Laser N = 240 Aflibercept N = 226 Observation N = 236 Prior Treatment for DME Anti-VEGF Focal/Grid Laser Prior PRP Recent or planned DME treatment in fellow eye* 5% 12% 7% 6% 10% 5% 6% 10% 4% 39% 38% 38% 12 * Randomization stratification factor

  13. Ocular Baseline Characteristics Initiation With Laser N = 240 Aflibercept N = 226 Observation N = 236 E-ETDRS VA Letter Score Mean 85 20% 46% 34% 85 24% 38% 38% 85 22% 42% 36% 89 (20/16 or better) 88 to 84 (20/20) 83 to 79 (20/25) OCT CST ( m), mean (Stratus Equivalent) 314 306 314 13

  14. Visits Initiation With Laser N = 240 N = 226 5 N = 212 6 N = 212 11 Aflibercept N = 226 N = 210 11 N = 205 7 N = 205 18 Observation N = 236 N = 220 6 N = 208 6 N = 208 12 Number of Visits Year 1 Median Year 2 Median Cumulative Over 2 Years Median 14

  15. Visual Acuity (VA) 15

  16. 5-Letter Loss At 2 Years Primary Outcome Treatment Group Comparisons Observed Data P Relative Risk CI Value Aflibercept vs. Laser % of Eyes 0.88 0.57-1.35 .79 Aflibercept vs. Observation 0.83 0.55-1.27 .79 19% 17% 16% Laser vs. Observation 0.95 0.64-1.41 .79 Aflibercept Laser Observation N = 205 N = 212 N = 208 16

  17. 10-Letter Loss At 2 Years Treatment Group Comparisons Observed Data P Relative Risk CI Value Aflibercept vs. Laser % of Eyes 1.13 0.59-2.17 .83 Aflibercept vs. Observation 1.21 0.62-2.36 .83 9% 7% 7% Laser vs. Observation 1.08 0.54-2.13 .83 Aflibercept Laser Observation N = 205 N = 212 N = 208 17

  18. 5-Letter Gain at 2 Years Treatment Group Comparisons Observed Data P Relative Risk CI Value Aflibercept vs. Laser % of Eyes 1.13 0.82-1.55 .46 Aflibercept vs. Observation 27% 25% 21% 1.30 0.86-1.98 .40 Laser vs. Observation 1.15 0.81-1.64 .46 Aflibercept Laser Observation N = 205 N = 212 N = 208 18

  19. 84 Letters (20/20 or Better) at 2 Years Treatment Group Comparisons Observed Data P 77% Relative Risk CI Value 71% 66% Aflibercept vs. Laser % of Eyes 1.11 0.97-1.27 .15 Aflibercept vs. Observation 1.18 1.01-1.37 .03 Laser vs. Observation 1.06 0.93-1.20 .40 Aflibercept Laser Observation N = 205 N = 212 N = 208 19

  20. VA Letter Score at 2 Years 20/25 or Better 100% 80% 66 71 % of Eyes 86% 77 86% 84% 60% 40% 20 13 20% 9 15 13 13 0% Aflibercept N = 205 Laser Observation N = 208 N = 212 78 (20/32) or Worse 83-79 (20/25) 84 (20/20) or Better 20

  21. Mean VA Letter Score At 2 Years 95 VA Letter Score (~Snellen Equivalent) Aflibercept Laser Observation 90 86.0 (20/20) 85.3 (20/20) 85 84.2 (20/20) 80 N = 226 N = 240 N = 236 N = 205 N = 212 N = 208 75 8-Week 2-Year 1-Year Visit 21 Error bars represent 95% confidence Intervals

  22. Mean VA Letter Score Change from Baseline 10 Mean VA Letter Score Change Aflibercept Laser Observation 5 +2.1 +0.1 0 0 1 Year: Adjusted Treatment Group Comparisons Aflibercept vs. Laser:2.1 (0.9 to 3.2); P <.001 Aflibercept vs. Observation: 2.2 (1.0 to 3.5); P <.001 Laser vs. Observation:0.1 (-0.9 to 1.2); P = .82 -5 N = 226 N = 240 N = 236 8-Week N = 205 N = 212 N = 208 2-Year -10 1-Year Visit 22 Error bars represent 95% confidence Intervals

  23. Mean VA Letter Score Change from Baseline 10 Mean VA Letter Score Change Aflibercept Laser Observation 5 +0.9 +0.1 0 -0.4 2 Years: Adjusted Treatment Group Comparisons Aflibercept vs. Laser:1.0 (-0.4 to 2.5); P = .21 Aflibercept vs. Observation: 1.3 (-0.3 to 2.8); P = .14 Laser vs. Observation:0.2 (-1.0 to 1.5); P = .70 1-Year -5 N = 226 N = 240 N = 236 8-Week N = 205 N = 212 N = 208 2-Year -10 Visit 23 Error bars represent 95% confidence Intervals

  24. Mean Change in VA Letter Score Over 2 Years (Area Under the Curve) Exploratory Analysis AUC Treatment Group Comparisons Mean Difference Aflibercept vs. Laser Aflibercept vs. Observation Laser vs. Observation Mean Change in Letter Score Over 2 Years P CI Value Aflibercept 1.9 (1.0, 2.8) <.001 1.5 Laser 2.1 (1.1, 3.1) <.001 0.0 Observation 0.2 (-0.7, 1.0) .73 -0.4 24

  25. Central Subfield Thickness (CST) 25

  26. Mean Change in OCT CST from Baseline 25 1 Year: Adjusted Treatment Group Comparisons Aflibercept vs. Laser: -22 (-34 to -11); P <.001 Aflibercept vs. Observation: -28 (-41 to -15); P <.001 Laser vs. Observation: -6 (-17 to 6); P = .34 Mean Change in OCT CST 0 -25 -25 -30 -50 -50 Aflibercept Laser 1-Year Visit Observation -75 8-Week 2-Year N = 226 N = 240 N = 236 N = 205 N = 212 N = 208 Error bars represent 95% confidence Intervals

  27. Mean Change in OCT CST from Baseline 25 2 Year: Adjusted Treatment Group Comparisons Aflibercept vs. Laser: -12 (-24 to 1); P = .07 Aflibercept vs. Observation: -13 (-27 to 1); P = .07 Laser vs. Observation: -1 (-13 to 11); P = .82 Mean Change in OCT CST 0 -42 -25 -41 -50 -48 Aflibercept Laser 1-Year Visit Observation -75 8-Week 2-Year N = 226 N = 240 N = 236 N = 205 N = 212 N = 208 Error bars represent 95% confidence Intervals

  28. DME Treatment 28

  29. Time to First Aflibercept Injection (Laser and Observation Groups) Cumulative Probability, % Laser vs. Observation Hazard Ratio: 0.66 (95% CI, 0.47-0.92) P = .01 36% 28% 26% 13% Weeks # of Eyes at Risk N = 236 N = 240 N = 157 N = 202 N = 132 N = 156 29

  30. Aflibercept Treatment for DME Initiation With Laser N = 240 N = 226 0 N = 212 0 N = 212 0 Aflibercept N = 226 N = 210 6 N = 205 1 N = 205 8 Observation N = 236 N = 220 0 N = 208 0 N = 208 0 Number of Injections Year 1 Median (IQR) Year 2 Median (IQR) Cumulative Over 2 Years Median (IQR) Note: Injection adherence was 98% in each group. 30

  31. Aflibercept Treatment for DME (Eyes receiving at least one injection) Initiation With Laser N = 240 N = 56 7 Aflibercept N = 226 N = 205 8 Observation N = 236 N = 76 9 Cumulative Over 2 Years* Median 31 * 2-year completers only

  32. Number of Injections Over 2 Years 74 63 % of Participants 39 25 18 18 13 13 12 7 5 5 4 4 0 Aflibercept (N=205) Laser (N=212) Observation (N=208) 0 1 to 4 5 to 8 9 to 12 13 Number of Injections 32 * 2-year completers only

  33. Aflibercept Treatment for DME Initiation With Laser N = 240 Aflibercept N = 226 Observation N = 236 Indication for first injection, N Decrease of 10 Letters - 37 44 Decrease of 5 to 9 letters at two consecutive visits - 19 34 33

  34. Safety 34

  35. Ocular Adverse Events Initiation With Laser N = 240 0 Aflibercept N = 226 0 Observation N = 236 0 P Value Endophthalmitis >.99 Any retinal detachment <1% <1% 0 .32 Cataract surgery 2% 2% 2% .94 Vitreous hemorrhage 4% 3% 2% .66 Ocular inflammation <1% 0 <1% .21 IOP elevation 8% 6% 3% .02 35

  36. APTC* Systemic Adverse Events Initiation With Laser N = 240 Aflibercept N = 226 Observation N = 236 P Value Nonfatal myocardial infarction Nonfatal stroke Death due to potential vascular or unknown cause Any event <1% <1% <1% .75 2% 3% 2% .84 4% 3% 1% .19 7% 5% 3% .28 36 *APTC = Antiplatelet Trialists Collaboration

  37. Summary In this cohort of individuals with center-involved DME and good visual acuity (> 20/25): No difference in rates of 1 or more lines of VA loss at 2 years among eyes initiating management with aflibercept, laser or observation All three management strategies resulted in mean VA at 2 years of 20/20 Proportion of eyes 20/20 or better was significantly greater with aflibercept (77%) than observation (66%) Proportion of eyes 20/25 or better was similar in each group (~85%) Majority of eyes in laser group (~3/4) and observation group (~2/3) did not receive aflibercept during study 37

  38. Discussion Study did not compare monotherapies; study did compare 3 different management strategies Eyes were followed carefully; aflibercept was initiated in the laser and observation groups if vision decreased by 1 line at 2 consecutive visits or 2 or more lines at 1 visit. Changes on OCT did not trigger aflibercept initiation Primary outcome was loss of 5 or more letters ( 1 line) Likely clinical relevant in eyes with good vision Unlikely due to chance variation 38

  39. Conclusion Among eyes with CI-DME and good VA, no significant difference in VA loss at 2 years whether eyes were initially managed with aflibercept, or with laser photocoagulation or observation and given aflibercept only if VA worsened. Given the costs and risk associated with interventions, observation without treatment unless VA worsens may be a reasonable strategy for these eyes. 39

  40. CW Baker and coauthors Effect of Initial Management With Aflibercept vs Laser Photocoagulation vs Observation on Vision Loss Among Patients With Diabetic Macular Edema Involving the Center of the Macula and Good Visual Acuity: A Randomized Clinical Trial Available at jama.com and on The JAMA Network Reader at mobile.jamanetwork.com jamanetwork.com

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