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New Concepts on Panretinal Photocoagulation for Proliferative Diabetic Retinopathy with highlights from the DRCR Network 1 Neil M. Bressler, MD The James.

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Presentation on theme: "New Concepts on Panretinal Photocoagulation for Proliferative Diabetic Retinopathy with highlights from the DRCR Network 1 Neil M. Bressler, MD The James."— Presentation transcript:

1 New Concepts on Panretinal Photocoagulation for Proliferative Diabetic Retinopathy with highlights from the DRCR Network 1 Neil M. Bressler, MD The James P. Gills Professor of Ophthalmology; Chief, Retina Division – Wilmer Eye Institute, Johns Hopkins University School of Medicine Baltimore, USA

2 Disclosures  Off-label use of drugs or devices: ranibizumab, bevacizumab, intravitreal triamcinolone  Data from human research is presented  Genentech (provided the ranibizumab) and Allergan, Inc. (provided the triamcinolone) for the study and collaborated in a manner consistent with the DRCR.net Industry Collaboration Guidelines, the DRCR.net had complete control over the design of the protocol, ownership of the data, and all editorial content of presentations and publications related to the protocol. 2

3 Financial Disclosures 3 Grants to investigators at The Johns Hopkins University are negotiated and administered by the School of Medicine) which receives the grants, through the Office of Research Administration. Individual investigators who participate in sponsored projects are not directly compensated by the sponsor, but may receive salary or other support from the institution to support their effort on the projects. Dr. Neil Bressler is Principal Investigator of grants at The Johns Hopkins University sponsored by the following entities (not including the National Institutes of Health): Abbott Medical Optics Inc.; Allergan; Bausch & Lomb; Carl Zeiss Meditec; EMMES Corporation; ForSight Labs, LLC; Genentech; Genzyme Corporation; Lumenis; Notal Vision; Novartis; Ora, Inc.; QLT Inc.; Regeneron; and Steba Biotech. Dr. Susan Bressler (spouse) is co-investigator of grants at The Johns Hopkins University sponsored by the following entities (not including the National Institutes of Health): Genentech; Notal Vision; Novartis. Dr. Susan Bressler is presently a consultant for the following entities: GlaxoSmithKline.

4 Thank you to the Diabetic Retinopathy Clinical Research Network (DRCR.net) for much of the content included in this presentation. Many of the DRCR.net slides and publications and data are available at no charge at the DRCR.net public web site at

5 Panretinal photocoagulation in the absence of diabetic macular edema Panretinal photocoagulation in the presence of diabetic macular edema (and therefore, typically also treated with focal/grid laser until recently) Panretinal photocoagulation in an era of anti-VEGF drugs for proliferative diabetic retinopathy Topics

6 Protocol Update: Demonstrating Life Cycle of Protocols in a Network 6 Recruitment Follow-Up

7 Development of DME Following Panretinal Scatter Photocoagulation Given in 1 or 4 Sittings in Eyes Without DME at Initiation of PRP 7 Diabetic Retinopathy Clinical Research Network. Arch Ophthalmol. 2009;127: Writing Committee: Lead Authors: Alexander J. Brucker, Haijing Qin. Additional Members (Alphabetical): Andrew N. Antoszyk, Roy W. Beck, Neil M. Bressler, David J. Browning, Michael J. Elman, Adam R. Glassman, Jeffrey G. Gross, Craig Kollman, John A. Wells III.

8 Development of DME Following Panretinal Scatter Photocoagulation Given in 1 or 4 Sittings (Protocol F) 8 1 Sitting N=84 4 Sittings N=71 P Value* Median baseline CSF thickness Median change from baseline (microns) at follow-up 3 days 4 weeks 17 weeks 34 weeks *P values are based on van der Waerden scores >300 spots q 4 wks Over 12 wks NOT randomized

9 Development of DME Following Panretinal Scatter Photocoagulation Given in 1 or 4 Sittings (Protocol F) 9 1 Sitting N=84 4 Sittings N=71 P Value* Median baseline CSF thickness Median change from baseline (microns) at follow-up 3 days weeks weeks weeks *P values are based on van der Waerden scores

10 Development of DME Following Panretinal Scatter Photocoagulation Given in 1 or 4 Sittings (Protocol F) 10 Visual Acuity 1 Sitting N=84 4 Sittings N=71 P Value* Median baseline (letter score) 85 (~20/20)83 (~20/20) Median change from baseline (letters) 3 days weeks weeks weeks *P values are based on van der Waerden scores

11 Summary 11  PRP in 1 sitting vs. 4 sittings spread over 12 weeks:  Clinically meaningful differences are unlikely in OCT thickness or visual acuity  PRP for diabetic retinopathy can be safely administered in 1 sitting in patients with good VA and no pre- existing center-involved ME  Although nearly half of 1-sitting PRP used retrobulbar anesthetic

12 Panretinal photocoagulation in the absence of diabetic macular edema Panretinal photocoagulation in the presence of diabetic macular edema (and therefore, typically also treated with focal/grid laser until recently) Panretinal photocoagulation in an era of anti-VEGF drugs for proliferative diabetic retinopathy Topics

13 Protocol Update: Demonstrating Life Cycle of Protocols in a Network 13 Recruitment Follow-Up

14 The Diabetic Retinopathy Clinical Research Network Randomized Trial Evaluating Short-Term Effects of Intravitreal Ranibizumab or Triamcinolone Acetonide on Diabetic Macular Edema Following Panretinal Photocoagulation Retina 2011 Supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services EY14231, EY14229, EY

15 Background PRP in Eyes with Central DME 15  Reported side effects of PRP include: Worsening macular edema and loss of visual acuity (prior to OCT) DRCR.net reported PRP in 1 or 4 sittings, respectively, results in median +14 or +15 µm increase in OCT CSF (25 th, 75 th percentile = +5 or +6, +20 or +34 µm) with little decreased acuity 17 weeks after initiating PRP in eyes without central DME Is change in OCT CSF and change in visual acuity similar in eyes receiving PRP with central DME which around the same time also receive focal/grid laser for the DME?

16 Background PRP in Eyes with Central DME 16  Focal/grid laser of central DME in absence of prompt PRP usually associated with short term improvement (at 16 weeks) of macular edema with little change in visual acuity Protocol N Median Change in OCT Central Subfield Thickness (25 th, 75 th quartiles) Median Change in Visual Acuity (25 th, 75 th quartiles) Protocol B (-90, 13)2 (-4, 7) Protocol K (-61, 13)1 (-3, 6) Protocol I (-101, 10)2 (-3, 8)

17 Background PRP in Eyes with Central DME 17  What if some eyes with central DME receiving PRP at the time of focal/grid laser have at least short term substantial worsening of macular edema and visual acuity loss,... ... then reducing the proportion of eyes with worsening of macular edema and visual acuity loss following PRP could improve quality of life for individuals undergoing this therapy, in the short term

18 18 Laser-Ranibizumab-Triamcinolone+PRP Randomized Clinical Trial for DME Laser-Ranibizumab-Triamcinolone+PRP Randomized Clinical Trial for DME Study Objective Evaluate short term effects of intravitreal ranibizumab or intravitreal triamcinolone on exacerbation of macular edema and associated visual acuity loss in eyes requiring PRP for severe NPDR or PDR and receiving focal/grid laser for center-involved DME.

19 Study Design 19 Primary outcome: Change in visual acuity from baseline to 14 weeks (intent to treat analysis) At least 1 eye meeting all of the following criteria:  Severe NPDR or PDR requiring prompt PRP  Presence of central DME on clinical exam and CST on OCT ≥250 microns  Best corrected E-ETDRS visual acuity letter score ≥24 (~20/320 or better) Randomized, multi-center clinical trial Sham+ Focal/Grid/PRP Laser Sham+ Focal/Grid/PRP Laser Ranibizumab+ Focal/Grid/PRP Laser Ranibizumab+ Focal/Grid/PRP Laser Triamcinolone+ Focal/Grid/PRP Laser Triamcinolone+ Focal/Grid/PRP Laser

20 Follow-up Schedule Weeks & 56 Weeks 34 Weeks & 56 Weeks 1 st injection at baseline Safety visit 3-10 days Focal/grid laser 3-10 days Initial PRP (following focal/grid ) 3-14 days 1 st injection at baseline Safety visit 3-10 days Focal/grid laser 3-10 days Initial PRP (following focal/grid ) 3-14 days Safety follow-up visits 14 Weeks 4 Weeks Baseline to 2 Weeks Baseline to 2 Weeks 2 nd injection (ranibizumab for ranibizumab group and sham for sham and triamcinolone groups) Follow-up visit 2 nd injection (ranibizumab for ranibizumab group and sham for sham and triamcinolone groups) Follow-up visit Primary outcome visit Sham, Ranibizumab Or Triamcinolone

21 21 Baseline Characteristics Sham+ Focal/Grid & PRP N = 123 Ranibizumab+ Focal/Grid & PRP N = 113 Triamcinolone+ Focal/Grid & PRP N = 109 Median E-ETDRS © visual acuity letter score (Snellen equivalent) 67 (20/50)68 (20/50)67 (20/50) Median OCT CSF thickness (µm) No prior treatment for DME 65%66%

22 22 Additional Treatment for DME Sham+ Focal/Grid/PRP Laser N = 123 Ranibizumab+ Focal/Grid/PRP Laser N = 113 Triamcinolone+ Focal/Grid/PRP Laser N = 109 Prior to 14 weeks Eyes with additional treatments weeks to 56 weeks Eyes with additional treatments Additional treatment* Bevacizumab (+/- Laser) Ranibizumab (+/- Laser) 133 Triamcinolone (+/- Laser) Laser Vitrectomy 210 Bevacizumab+Triamcinolone (+/- Laser) 202 Triamcinolone+Vitrectomy 010 Eyes with non-protocol anti- VEGF trt (# of trts applied) 28 (39)23 (32)17 (32) *Number of eyes, each combination of treatment only counted once

23 23 Primary Outcome Change in Visual Acuity at 14 Weeks Primary Outcome Change in Visual Acuity at 14 Weeks Change in visual acuity (letters) Sham+ Focal/Grid/PRP Laser N = 123 Ranibizumab+ Focal/Grid/PRP Laser N = 113 Triamcinolone+ Focal/Grid/PRP Laser N = 109 Mean Difference in mean change from Sham +Focal/Grid/PRP Laser [P Value]* +5.6 [P < 0.001] +6.7 [P < 0.001] *Adjusted for baseline visual acuity, number of planned PRP sittings, and correlation between 2 study eyes.

24 Mean Change in Visual Acuity* from Baseline 24 Safety Phase (DME treatment at investigator discretion) Safety Phase (DME treatment at investigator discretion) Randomized Phase (DME treatment according to protocol) * Values that were ±30 letters were assigned a value of 30

25 Change in Retinal Thickening at 14 Weeks* 25 Change in OCT Central Subfield Thickening * Sham+ Focal/Grid/PRP Laser N = 115 Ranibizumab+ Focal/Grid/PRP Laser N = 100 Triamcinolone+ Focal/Grid/PRP Laser N = 103 Mean change from baseline (µm) Difference in mean change from Sham+ Focal/Grid/PRP Laser [P Value] † -35 [P = 0.007] -100 [P < 0.001] Thickness ≥10% increase with at least a 25 µm increase from baseline 38%17%10% Thickness <250 µm with at least a 25 µm decrease from baseline 10%17%27% * Missing (or ungradeable) data as follows for the sham+focal/grid/PRP laser group, ranibizumab+focal/grid/PRP laser group, and triamcinolone+focal/grid/PRP laser groups, respectively: 3, 3, 2 † Adjusted for baseline OCT retinal thickness and visual acuity, number of planned PRP sittings, and correlation between 2 study eyes. ~ -30um in absence of PRP

26 Correlation between Visual Acuity and Central Subfield Thickness at 14 Weeks 26 Sham+ Focal/Grid/PRP Laser Ranibizumab+ Focal/Grid/PRP Laser Triamcinolone+ Focal/Grid/PRP Laser Central subfield thickness ≥10% increase with at least a 25 µm increase from baseline Central subfield thickness ≥10% increase with at least a 25 µm increase from baseline AND with concordant decreases in visual acuity of ≥10 letters at 14 weeks 15 (34%)2 (12%)1 (10%)

27 27 Major Ocular Adverse Events Prior to the 14-Week Visit Adverse events prior to the 14-week visit Sham+ Focal/Grid/PR P Laser N = 133 Ranibizumab+ Focal/Grid/PRP Laser N = 116 Triamcinolone+ Focal/Grid/PRP Laser N = 115 Number of injections Endophthalmitis*01 (0.9%)0 Ocular vascular event000 Traction retinal detachment 3 (2%)1 (1%) Vitrectomy1 (1%)0 Vitreous Hemorrhage16 (12%)6 (5%)7 (6%) * One case related to study drug injection in the ranibizumab+focal/grid/PRP laser group.

28 28 Elevated Intraocular Pressure/Glaucoma Prior to the 14-Week Visit Sham+ Focal/Grid/PRP Laser N = 133 Ranibizumab+ Focal/Grid/PRP Laser N = 116 Triamcinolone+ Focal/Grid/PRP Laser N = 115 Number of injections Elevated Intraocular Pressure/Glaucoma Increase ≥10 mmHg from baseline 3 (2%)020 (17%) IOP ≥30 mmHg 2 (2%)05 (4%) Initiation of IOP-lowering meds at any visit* 2 (2%)0 Number of eyes meeting ≥1 of the above 3 (2%)020 (17%) Glaucoma surgery000 *Excludes eyes with IOP lowering medications at baseline

29 Cataract Surgery During Follow-up 29 Sham+ Focal/Grid/PRP Laser Ranibizumab+ Focal/Grid/PRP Laser Triamcinolone+ Focal/Grid/PRP Laser Prior to 14 week visit Phakic at baselineN = 120N = 93N = 105 Eyes that had cataract surgery to 56 week visit Phakic at 14 weeksN = 119N = 91N = 102 Eyes that had cataract surgery 2 (2%)3 (3%)6 (6%)

30 Number of Deaths 30 Sham N = 133 Ranibizumab N = 116 Triamcinolone N = 115 Deaths332

31 Cardiovascular or Cerebrovascular Events According to Antiplatelet Trialists’ Collaboration through 56 Weeks 31 ATC Event Sham N * = 102 Ranibizumab N * = 116 Triamcinolone N * = 115 Non-fatal myocardial infarction 1 (1%)3 (3%)0 Non-fatal cerebrovascular accident-ischemic or hemorrhagic (or unknown) 1 (1%)3 (3%)4 (3%) Vascular death (from any potential vascular or unknown cause) 2 (2%)3 (3%)0 Any APTC event 4 (4%)8 † (7%)4 (3%) * N=Number of Study Participants. Study participants with 2 study eyes are assigned to the non-sham group. Multiple events within a study participant are only counted once per event. † 1event occurred between baseline and 4 week injections, 1 event occurred about 3 weeks after the 4 week injection, and the other events from the remaining 6 study participants occurred over 4 weeks after the 4 week injection

32 Cardiovascular Events According to Antiplatelet Trialists’ Collaboration* through 56 Weeks 32 Safety Phase (DME treatment at investigator discretion) *Antiplatelet Trialists’ Collaboration. BMJ Jan 8;308(6921): Non-fatal cerebrovascular accidents include ischemic, hemorrhagic or unknown. Vascular death includes any potential vascular or unknown cause. Vascular or unknown death Randomized Phase (DME treatment according to protocol) Triamcinolone Ranibizumab Sham

33 Summary Randomized Phase of Trial  14 week primary outcome visit: On average, both ranibizumab and triamcinolone statistically significantly improve visual acuity and retinal thickness compared to sham injection in eyes with central DME receiving focal/grid laser and requiring prompt PRP Safety Phase of Trial  14 week to 56 week visits: Differences in visual acuity and retinal thickness outcomes above no longer significant, BUT no long- term harm from these “acute” management strategies were found 33

34 Summary Macular Edema after Prompt PRP in Eyes with Central DME Also Receiving Focal/Grid Laser – Sham Injection Group  Focal/grid laser of central DME in absence of prompt PRP usually associated decreased macular edema by 16 weeks 34 Protocol Median Change in OCT Central Subfield Thickness from Baseline to 16 Weeks (25 th, 75 th quartiles) Median Change in Visual Acuity from Baseline to 16 Weeks (25 th, 75 th quartiles) Protocol B -33 (-90, 13)2 (-4, 7) Protocol K -27 (-61, 13)1 (-3, 6) Protocol I -34 (-101, 10)2 (-3, 8)

35 Summary Macular Edema after Prompt PRP in Eyes with Central DME Also Receiving Focal/Grid Laser – Sham Injection Group  Focal/grid laser of central DME in absence of prompt PRP usually associated decreased macular edema by 16 weeks 35 Protocol Median Change in OCT Central Subfield Thickness from Baseline to 16 Weeks (25 th, 75 th quartiles) Median Change in Visual Acuity from Baseline to 16 Weeks (25 th, 75 th quartiles) Protocol B -33 (-90, 13)2 (-4, 7) Protocol K -27 (-61, 13)1 (-3, 6) Protocol I -34 (-101, 10)2 (-3, 8) Protocol J (Sham group only at 14 weeks) 0 (-80, +70)-2 (-8, +3)

36 Summary Safety  Ranibizumab: Endophthalmitis: one eye receiving ranibizumab Long term (>1 yr) safety of ranibizumab injections in persons with characteristics similar to those enrolled in this protocol remains largely unknown  Triamcinolone: Associated with increased risk of elevated IOP between 14 and 56 weeks; even with only one treatment at baseline Unlike prior studies, not associated with higher incidence of cataract surgery oWhy? Only 1 injection? Younger cohort? Lower enthusiasm to operate on cataracts in this advance DR cohort? Other factors? 36

37 Summary Safety  This study did not identify an increased risk of traction retinal detachments beyond that which could be attributed to chance alone.  Cerebrovascular or cardiovascular events did not occur with a difference in frequency among the 3 groups that could not be attributed to chance alone – further study indicated. 37

38 Conclusions  Eyes with central DME receiving prompt PRP at time of focal/grid laser for DME appear more likely to have increased macular edema and visual acuity loss in short term than: Eyes without central DME receiving prompt PRP but no focal/grid laser Eyes with central DME receiving foca/grid laser but no prompt PRP 38

39 Conclusions  The risk of short-term exacerbation of macular edema and associated visual acuity loss following prompt PRP in eyes also receiving focal/grid laser for DME can be reduced by intravitreal triamcinolone or ranibizumab. Benefits were not maintained at 1 year, but study injections were discontinued after 1 (triamcinolone) or 2 (ranibizumab) injections 39

40 Panretinal photocoagulation in the absence of diabetic macular edema Panretinal photocoagulation in the presence of diabetic macular edema (and therefore, typically also treated with focal/grid laser until recently) Panretinal photocoagulation in an era of anti-VEGF drugs for proliferative diabetic retinopathy Topics

41 Protocol Update: Demonstrating Life Cycle of Protocols in a Network 41 Recruitment Follow-Up

42 Step Changes of Improvement/Worsening in Diabetic Retinopathy by Baseline Severity Change from Baseline to 1-Year Visit * Sham + Prompt Laser Ranibizumab + Prompt Laser or Deferred Laser Triamcinolone + Prompt Laser Baseline Severity: Moderately Severe NPDR or Better N = 150N = 182N = 80 Improved by ≥2 levels4%25% Worsened by ≥2 levels7%3% P value for comparison with Sham P =.08P =.17 * Photos were missing or ungradeable for 61 eyes in the sham + prompt laser group, 72 eyes in the ranibizumab groups, and 33 eyes in the triamcinolone + prompt laser group. NPDR = nonproliferative diabetic retinopathy.

43 Step Changes of Improvement/Worsening in Diabetic Retinopathy by Baseline Severity Change from Baseline to 1-Year Visit * Sham + Prompt Laser Ranibizumab + Prompt Laser or Deferred Laser Triamcinolone + Prompt Laser Baseline Severity: Moderately Severe NPDR or Better N = 150N = 182N = 80 Improved by ≥2 levels4%25% Worsened by ≥2 levels7%3% P value for comparison with Sham P =.08P =.17 Baseline Severity: Severe NPDR or Worse N = 83N = 121N = 70 Improved by ≥2 levels19%28%13% Worsened by ≥2 levels8%1%3% P value for comparison with Sham P =.03P =.17 * Photos were missing or ungradeable for 61 eyes in the sham + prompt laser group, 72 eyes in the ranibizumab groups, and 33 eyes in the triamcinolone + prompt laser group. NPDR = nonproliferative diabetic retinopathy.

44 Background  Current treatment for PDR is panretinal photocoagulation (PRP) Inherently destructive Adverse effects on visual function  Some eyes with PDR+DME now receive anti-VEGF as standard care for DME  Would initial treatment of PDR with intravitreal anti-VEGF delay or prevent need for PRP? 44

45 Study Objective and Treatment Groups Prompt PRP To determine if visual acuity outcomes at 2 years in eyes with PDR (with or without concurrent DME) that receive anti-VEGF therapy with deferred PRP are non- inferior to those in eyes that receive prompt PRP therapy. (Note: Study ranibizumab may be given as needed for DME using Protocol I retreatment as guidelines.) mg ranibizumab with deferred PRP

46 Important Secondary Objectives (assuming visual acuity outcomes are non-inferior)  Compare visual function outcomes (including Humphrey visual field testing and study participant self-reports of visual function)  Determine percent of eyes not requiring PRP when intravitreal anti-VEGF is given in the absence of prompt PRP  Compare safety outcomes  Perform cost effectiveness analysis 46

47 Panretinal photocoagulation in the absence of diabetic macular edema Panretinal photocoagulation in the presence of diabetic macular edema (and therefore, typically also treated with focal/grid laser until recently) Panretinal photocoagulation in an era of anti-VEGF drugs for proliferative diabetic retinopathy Topics

48 48

49 Risk of Severe Visual Loss or Vitrectomy Event Rate 5% 10% 0% Years P=0.43 Eyes with SNPDR or Early PDR Deferred Scatter Early Scatter Type 1 Diabetes

50 Risk of Severe Visual Loss or Vitrectomy Event Rate 5% 10% 0% Years P= Eyes with SNPDR or Early PDR Deferred Scatter Early Scatter Type 2 Diabetes

51 DRS Untreated Eye ETDRS Eyes With Proliferative Retinopathy Risk of Visual Acuity 20/200 or Worse 10% 20% 0% 30% Event Rate Years 5 40% Eyes Patients

52 DRS Untreated Eye ETDRS 10% 20% 0% 30% Event Rate Years 5 40% Eyes With Proliferative Retinopathy Risk of Visual Acuity 5/200 or Worse Eyes Patients


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