Neil M. Bressler, MD

New Concepts on Panretinal Photocoagulation for Proliferative Diabetic Retinopathywith highlights from the DRCR Network 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

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.

Financial Disclosures • 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.

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 www.drcr.net

Topics • 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

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

Development of DME Following Panretinal Scatter Photocoagulation Given in 1 or 4 Sittings in Eyes Without DME at Initiation of PRP Diabetic Retinopathy Clinical Research Network. Arch Ophthalmol. 2009;127:132-140. 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. 7

Development of DME Following Panretinal Scatter Photocoagulation Given in 1 or 4 Sittings (Protocol F) >300 spots q 4 wks Over 12 wks NOT randomized *P values are based on van der Waerden scores

Development of DME Following Panretinal Scatter Photocoagulation Given in 1 or 4 Sittings (Protocol F) *P values are based on van der Waerden scores

Summary • 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

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, EY018817

BackgroundPRP in Eyes with Central DME • 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 (25th, 75th 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?

BackgroundPRP in Eyes with Central DME • 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

BackgroundPRP in Eyes with Central DME • 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

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.

Study Design Randomized, multi-center clinical trial 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) Sham+ Focal/Grid/PRP Laser Ranibizumab+ Focal/Grid/PRP Laser Triamcinolone+ Focal/Grid/PRP Laser Primary outcome: Change in visual acuity from baseline to 14 weeks (intent to treat analysis)

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

Baseline Characteristics

Additional Treatment for DME *Number of eyes, each combination of treatment only counted once

Primary Outcome Change in Visual Acuity at 14 Weeks *Adjusted for baseline visual acuity, number of planned PRP sittings, and correlation between 2 study eyes.

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

Change in Retinal Thickening at 14 Weeks* ~ -30um in absence of PRP *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.

Major Ocular Adverse Events Prior to the 14-Week Visit * One case related to study drug injection in the ranibizumab+focal/grid/PRP laser group. 27

Elevated Intraocular Pressure/Glaucoma Prior to the 14-Week Visit 28 *Excludes eyes with IOP lowering medications at baseline

Cataract Surgery During Follow-up

Number of Deaths

Cardiovascular or Cerebrovascular Events According to Antiplatelet Trialists’ Collaboration through 56 Weeks • *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

Cardiovascular Events According to AntiplateletTrialists’ Collaboration* through 56 Weeks Vascular or unknown death Sham Ranibizumab Triamcinolone 4 14 34 56 Randomized Phase (DME treatment according to protocol) Safety Phase (DME treatment at investigator discretion) *Antiplatelet Trialists’ Collaboration. BMJ. 1994 Jan 8;308(6921):81-106. Non-fatal cerebrovascular accidents include ischemic, hemorrhagic or unknown. Vascular death includes any potential vascular or unknown cause.

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

SummaryMacular 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

SummarySafety • 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 • Why? Only 1 injection? Younger cohort? Lower enthusiasm to operate on cataracts in this advance DR cohort? Other factors?

SummarySafety • 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.

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

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

Step Changes of Improvement/Worsening in Diabetic Retinopathy by Baseline Severity *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.

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

Study Objective and Treatment Groups 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.) • Prompt PRP 0.5mg ranibizumab with deferred PRP 45

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

Risk of Severe Visual Loss or Vitrectomy Eyes with SNPDR or Early PDR Event Rate Deferred Scatter Type 1 Diabetes Early Scatter 10% 5% P=0.43 0% 0 1 2 3 4 5 Years

Risk of Severe Visual Loss or Vitrectomy Eyes with SNPDR or Early PDR Event Rate Deferred Scatter Type 2 Diabetes Early Scatter 10% 5% P=0.0001 0% 0 1 2 3 4 5 Years

Risk of Visual Acuity 20/200 or Worse Eyes With Proliferative Retinopathy Event Rate DRS Untreated Eye 40% 30% 20% ETDRS 10% Eyes Patients 0% 0 1 2 3 4 5 Years

Neil M. Bressler, MD

Neil M. Bressler, MD

Presentation Transcript

Kathryn E. Callahan, MD Helen M. Fernandez, MD, MPH Kirsten Feiereisel, MD William P. Moran, MD, MS Paula M. Podrazik, M

Moderator Neil Love, MD

CDR Elizabeth M. Hofmeister, MD* CDR Frank M. Bishop, MD* CAPT David J. Tanzer , MD**

David M. L. Sills 1 and Neil M. Taylor 2

Dr. Neil T. M. Hamilton Executive Director

Joseph M. Lane, MD

M. Akhalaia, MD, Microbiologist,

Carlos M. Luna MD

Robert M. Wachter, MD

Russell Vang, MD, and Brigitte M. Ronnett, MD

Carlos M. Luna MD

James M. McCabe, MD

Hemochromatosis Baghbanian M MD.

Organisation Chart Bressler Menü 2011

Gina M. Brown, MD

Susan Murphy ScD, OTR 1,2,4 Neil Alexander MD 1,3,4

M Kaleem Arshad MD

Lee Bressler

ali M. somily , MD

Glenn M. Amundson, MD - Retired Captain of the Medical Corps