neil m. bressler, md

New Concepts on Panretinal Photocoagulation for Proliferative

Diabetic Retinopathy

with highlights from the DRCR Network

1

Neil M. Bressler, MDThe 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 triamcinoloneData from human research is presentedGenentech (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.

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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.

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

• 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

Protocol Update:Demonstrating Life Cycle of Protocols in a Network

6Recruitment Follow-Up

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;127:132-140.

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.

Development of DME Following Panretinal Scatter Photocoagulation Given in 1 or 4

Sittings (Protocol F)

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1 SittingN=84

4 SittingsN=71 P Value*

Median baseline CSF thickness 207 198

Median change from baseline (microns) at follow-up

3 days4 weeks17 weeks34 weeks

*P values are based on van der Waerden scores

>300 spots q 4 wksOver 12 wks

NOTrandomized



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1 SittingN=84


Median baseline CSF thickness 207 198

Median change from baseline (microns) at follow-up

3 days +9 +5 0.014 weeks +13 +5 0.00317 weeks +14 +15 0.0834 weeks +14 +22 0.06




10

Visual Acuity 1 SittingN=84


Median baseline (letter score) 85 (~20/20) 83 (~20/20)

Median change from baseline (letters)

3 days -3 -1 0.0054 weeks -1 -1 0.3717 weeks -1 -1 0.6634 weeks 0 -2 0.006


Summary

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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




Topics

The Diabetic Retinopathy Clinical Research Network

Randomized Trial Evaluating Short-Term Effects of Intravitreal Ranibizumab or Triamcinolone Acetonide on Diabetic Macular Edema Following Panretinal

PhotocoagulationRetina 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

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BackgroundPRP in Eyes with Central DME

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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?


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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 (25th, 75th quartiles)

Median Change in Visual Acuity

(25th, 75th quartiles)

Protocol B 311 -33 (-90, 13) 2 (-4, 7)Protocol K 119 -27 (-61, 13) 1 (-3, 6)Protocol I 268 -34 (-101, 10) 2 (-3, 8)


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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

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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

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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 PRPPresence of central DME on clinical exam and CST

on OCT ≥250 micronsBest corrected E-ETDRS visual acuity letter score

≥24 (~20/320 or better)

Randomized, multi-center clinical trial

Sham+Focal/Grid/PRP

Laser

Ranibizumab+Focal/Grid/PRP

Laser

Triamcinolone+Focal/Grid/PRP

Laser

Follow-up Schedule

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34 Weeks &56 Weeks

• 1st 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

• 2nd injection (ranibizumab for ranibizumab group and sham for sham and triamcinolone groups)

• Follow-up visit

• Primary outcome visit

Sham, Ranibizumab Or Triamcinolone

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Baseline CharacteristicsSham+

Focal/Grid & PRP

N = 123

Ranibizumab+Focal/Grid &

PRPN = 113

Triamcinolone+Focal/Grid &

PRPN = 109

Median E-ETDRS©

visual acuity letter score (Snellen equivalent) 67 (20/50) 68 (20/50) 67 (20/50)

Median OCT CSF thickness (µm) 355 352 359

No prior treatment for DME 65% 66% 66%

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Additional Treatment for DMESham+

Focal/Grid/PRP Laser

N = 123


LaserN = 113


LaserN = 109

Prior to 14 weeksEyes with additional treatments 0 0 0

14 weeks to 56 weeksEyes with additional treatments 71 48 45

Additional treatment*Bevacizumab (+/- Laser) 22 17 9Ranibizumab (+/- Laser) 1 3 3Triamcinolone (+/- Laser) 10 12 7Laser 31 10 21Vitrectomy 2 1 0Bevacizumab+Triamcinolone (+/- Laser) 2 0 2

Triamcinolone+Vitrectomy 0 1 0

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

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Primary OutcomeChange in Visual Acuity at 14 Weeks

Change in visual acuity (letters)

Sham+Focal/Grid/PRP

LaserN = 123


LaserN = 113


LaserN = 109

Mean -4 +1 +2

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.

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

000 444 141414 343434 565656

Mea

n C

hang

e in

Vis

ual A

cuity

fr

om B

asel

ine

(lette

r sco

re)

-5

-4

-3

-2

-1

0

1

2

3

4

5

Sham+Focal/Grid/PRP LaserRanibizumab+Focal/Grid/PRP LaserTriamcinolone+Focal/Grid/PRP Laser

Change in Retinal Thickening at 14 Weeks*

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Change in OCT Central Subfield Thickening*

Sham+Focal/Grid/PRP

LaserN = 115


LaserN = 100


LaserN = 103

Mean change from baseline (µm) -5 -39 -92

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 inabsence of PRP

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Major Ocular Adverse Events Prior to the 14-Week Visit

Adverse events prior to the 14-week visit

Sham+Focal/Grid/PRP Laser

N = 133


LaserN = 116


LaserN = 115

Number of injections 227 115

Endophthalmitis* 0 1 (0.9%) 0

Ocular vascular event 0 0 0

Traction retinal detachment

3 (2%) 1 (1%) 1 (1%)

Vitrectomy 1 (1%) 0 1 (1%)

Vitreous Hemorrhage 16 (12%) 6 (5%) 7 (6%)

* One case related to study drug injection in the ranibizumab+focal/grid/PRP laser group.

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Elevated Intraocular Pressure/Glaucoma Prior to the 14-Week Visit

Sham+Focal/Grid/PRP

LaserN = 133


LaserN = 116


LaserN = 115

Number of injections 227 115Elevated Intraocular Pressure/GlaucomaIncrease ≥10 mmHg from baseline 3 (2%) 0 20 (17%)

IOP ≥30 mmHg 2 (2%) 0 5 (4%)Initiation of IOP-lowering meds at any visit* 2 (2%) 0 2 (2%)

Number of eyes meeting ≥1 of the above 3 (2%) 0 20 (17%)

Glaucoma surgery 0 0 0

*Excludes eyes with IOP lowering medications at baseline

Cataract Surgery During Follow-up

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Sham+Focal/Grid/PRP

Laser


Laser


Laser

Prior to 14 week visitPhakic at baseline N = 120 N = 93 N = 105Eyes that had cataract surgery 0 0 0

14 to 56 week visitPhakic at 14 weeks N = 119 N = 91 N = 102Eyes that had cataract surgery 2 (2%) 3 (3%) 6 (6%)

Number of Deaths

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ShamN = 133

RanibizumabN = 116

TriamcinoloneN = 115

Deaths 3 3 2

Cardiovascular or Cerebrovascular Events According to Antiplatelet Trialists’

Collaboration through 56 Weeks

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ATC Event

Sham N* = 102

Ranibizumab N* = 116

TriamcinoloneN* = 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

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

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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.

Vascular or unknown death

Randomized Phase(DME treatment according to protocol)

Non-fatal myocardial infarctionNon-fatal cerebrovascular accidentVascular or unknown death

Triamcinolone

Ranibizumab

Sham

4 14 34 56

SummaryRandomized 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

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

34

Protocol

Median Change in OCT Central Subfield Thickness from

Baseline to 16 Weeks (25th, 75th quartiles)

Median Change in Visual Acuity from


Protocol B -33 (-90, 13) 2 (-4, 7)Protocol K -27 (-61, 13) 1 (-3, 6)Protocol I -34 (-101, 10) 2 (-3, 8)

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

35

Protocol

Median Change in OCT Central Subfield Thickness from


Median Change in Visual Acuity from


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)

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 o Why? Only 1 injection? Younger cohort? Lower enthusiasm to

operate on cataracts in this advance DR cohort? Other factors? 36

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.

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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

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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




Topics

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

Change from Baseline to 1-Year Visit*

Sham + Prompt

Laser

Ranibizumab + PromptLaser or

Deferred Laser

Triamcinolone+ Prompt

Laser

Baseline Severity: Moderately Severe NPDR or Better N = 150 N = 182 N = 80

Improved by ≥2 levels 4% 25% 25%Worsened by ≥2 levels 7% 3% 3%P value for comparison with Sham P = .08 P = .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.

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

Change from Baseline to 1-Year Visit*

Sham + Prompt

Laser

Ranibizumab + PromptLaser or

Deferred Laser

Triamcinolone+ Prompt

Laser

Baseline Severity: Moderately Severe NPDR or Better N = 150 N = 182 N = 80


Baseline Severity: Severe NPDR or Worse N = 83 N = 121 N = 70


*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.

BackgroundCurrent 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?

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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.)

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0.5mg ranibizumab with deferred

PRP

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 outcomesPerform cost effectiveness analysis

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Topics

Risk of Severe Visual Loss or Vitrectomy

EventRate

5%

10%

0%10 2 3 4 5

Years

P=0.43

Eyes with SNPDR or Early PDR

Deferred Scatter

Early ScatterType 1 Diabetes

Risk of Severe Visual Loss or Vitrectomy

EventRate

5%

10%

0%10 2 3 4 5

Years

P=0.0001

Eyes with SNPDR or Early PDR

Deferred Scatter

Early ScatterType 2 Diabetes

DRSUntreated Eye

ETDRS

Eyes With Proliferative Retinopathy Risk of Visual Acuity 20/200 or Worse

10%

20%

0%

30%

EventRate

10 2 3 4Years

5

40%

EyesPatients

DRSUntreated Eye

ETDRS10%

20%

0%

30%

EventRate

10 2 3 4Years

5

40%

Eyes With Proliferative Retinopathy Risk of Visual Acuity 5/200 or Worse

EyesPatients

neil m. bressler, md

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