Transcript or 2 - Sociedad Chilena de Retina y Vitreo

New Concepts on Panretinal
Photocoagulation for Proliferative
Diabetic Retinopathy
with 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
1
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
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.
3
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
6
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
spots q 4 wks
NOT
Sittings (Protocol
F) >300
Over 12 wks
randomized
Median baseline CSF
thickness
1 Sitting
N=84
4 Sittings
N=71
207
198
P Value*
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
8
Development of DME Following Panretinal
Scatter Photocoagulation Given in 1 or 4
Sittings (Protocol F)
1 Sitting
N=84
4 Sittings
N=71
207
198
3 days
+9
+5
0.01
4 weeks
+13
+5
0.003
17 weeks
+14
+15
0.08
34 weeks
+14
+22
0.06
Median baseline CSF
thickness
P Value*
Median change from
baseline (microns) at
follow-up
*P values are based on van der Waerden scores
9
Development of DME Following Panretinal
Scatter Photocoagulation Given in 1 or 4
Sittings (Protocol F)
1 Sitting
N=84
4 Sittings
N=71
85 (~20/20)
83 (~20/20)
3 days
-3
-1
0.005
4 weeks
-1
-1
0.37
17 weeks
-1
-1
0.66
34 weeks
0
-2
0.006
Visual Acuity
Median baseline (letter
score)
P Value*
Median change from
baseline (letters)
*P values are based on van der Waerden scores
10
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 preexisting center-involved ME
 Although nearly half of 1-sitting PRP used
retrobulbar anesthetic
11
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
13
Recruitment
Follow-Up
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
14
Background
PRP 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?
15
Background
PRP 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
Protocol
Protocol B
Protocol K
Protocol I
N
311
119
268
Median Change
in OCT Central
Subfield
Thickness (25th,
75th quartiles)
Median Change
in Visual Acuity
(25th, 75th
quartiles)
-33 (-90, 13)
2 (-4, 7)
-27 (-61, 13)
1 (-3, 6)
-34 (-101, 10)
2 (-3, 8)
16
Background
PRP 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
17
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.
18
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)
19
Follow-up Schedule
Sham, Ranibizumab
Or Triamcinolone
Baseline to
2 Weeks
4 Weeks
•
•
•
•
1st injection at baseline
Safety visit 3-10 days
Focal/grid laser 3-10 days
Initial PRP (following focal/grid ) 3-14
days
• 2nd injection (ranibizumab for
ranibizumab group and sham for sham
and triamcinolone groups)
• Follow-up visit
14 Weeks
• Primary outcome visit
34 Weeks &
56 Weeks
• Safety follow-up visits
20
Baseline Characteristics
Sham+
Focal/Grid &
PRP
N = 123
Ranibizumab+
Focal/Grid &
PRP
N = 113
Triamcinolone+
Focal/Grid &
PRP
N = 109
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%
Median E-ETDRS©
visual acuity letter
score (Snellen
equivalent)
21
Additional Treatment for DME
Sham+
Ranibizumab+
Focal/Grid/PRP Focal/Grid/PRP
Laser
Laser
N = 123
N = 113
Triamcinolone+
Focal/Grid/PRP
Laser
N = 109
Prior to 14 weeks
Eyes with additional treatments
0
0
0
71
48
45
Bevacizumab (+/- Laser)
22
17
9
Ranibizumab (+/- Laser)
1
3
3
Triamcinolone (+/- Laser)
10
12
7
Laser
31
10
21
Vitrectomy
2
1
0
Bevacizumab+Triamcinolone (+/- Laser)
2
0
2
Triamcinolone+Vitrectomy
0
1
0
28 (39)
23 (32)
17 (32)
14 weeks to 56 weeks
Eyes with additional treatments
Additional treatment*
Eyes with non-protocol antiVEGF trt (# of trts applied)
*Number of eyes, each combination of treatment only counted once
22
Primary Outcome
Change in Visual Acuity at 14 Weeks
Change in visual
acuity (letters)
Mean
Difference in mean
change from Sham
+Focal/Grid/PRP
Laser [P Value]*
Sham+
Focal/Grid/PRP
Laser
N = 123
Ranibizumab+
Focal/Grid/PRP
Laser
N = 113
Triamcinolone+
Focal/Grid/PRP
Laser
N = 109
-4
+1
+2
+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.
23
Mean Change in Visual Acuity* from
Baseline
Mean Change in Visual Acuity
from Baseline (letter score)
5
4
Sham+Focal/Grid/PRP Laser
Ranibizumab+Focal/Grid/PRP Laser
Triamcinolone+Focal/Grid/PRP Laser
3
2
1
0
-1
-2
-3
-4
-5
0
4
14
34
Randomized Phase
(DME treatment according to protocol)
* Values
56
Safety Phase
Safety Phase
(DME treatment at investigator discretion)
(DME treatment at investigator discretion)
24
that were ±30 letters were assigned a value of 30
Change in Retinal Thickening at 14 Weeks*
Change in OCT
Central Subfield
Thickening*
Mean change from
baseline (µm)
Sham+
Ranibizumab+
Focal/Grid/PRP Focal/Grid/PRP
Laser
Laser
~ -30um in
N = 115 of PRP
N = 100
absence
-5
Difference in mean
change from Sham+
Focal/Grid/PRP Laser
[P Value] †
Triamcinolone+
Focal/Grid/PRP
Laser
N = 103
-39
-92
-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.
25
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
Number of injections
Ranibizumab+
Focal/Grid/PRP
Laser
N = 116
Triamcinolone+
Focal/Grid/PRP
Laser
N = 115
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%)
16 (12%)
6 (5%)
7 (6%)
Vitreous Hemorrhage
* 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
Sham+
Focal/Grid/PRP
Laser
N = 133
Number of injections
Ranibizumab+ Triamcinolone+
Focal/Grid/PRP Focal/Grid/PRP
Laser
Laser
N = 116
N = 115
227
115
Elevated Intraocular
Pressure/Glaucoma
Increase ≥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%)
3 (2%)
0
20 (17%)
0
0
0
Number of eyes
meeting ≥1 of the above
Glaucoma surgery
*Excludes eyes with IOP lowering medications at baseline
28
Cataract Surgery During Follow-up
Sham+
Focal/Grid/PRP
Laser
Ranibizumab+
Focal/Grid/PRP
Laser
Triamcinolone+
Focal/Grid/PRP
Laser
N = 120
N = 93
N = 105
0
0
0
Phakic at 14 weeks
N = 119
N = 91
N = 102
Eyes that had cataract
surgery
2 (2%)
3 (3%)
6 (6%)
Prior to 14 week
visit
Phakic at baseline
Eyes that had cataract
surgery
14 to 56 week visit
29
Number of Deaths
Sham Ranibizumab Triamcinolone
N = 133
N = 116
N = 115
Deaths
3
3
2
30
Cardiovascular or Cerebrovascular
Events According to Antiplatelet Trialists’
Collaboration through 56 Weeks
Sham
N* = 102
Ranibizumab Triamcinolone
N* = 116
N* = 115
ATC Event
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
31
Cardiovascular Events According to Antiplatelet
Trialists’ Collaboration* through 56 Weeks
Non-fatal myocardial infarction
Non-fatal cerebrovascular accident
Vascular or
or unknown
unknown death
death
Vascular
Sham
Ranibizumab
Triamcinolone
4
14
Randomized Phase
(DME treatment according to protocol)
34
56
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.
32
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 longterm harm from these “acute” management strategies
were found
33
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
Protocol
Median Change in OCT
Central Subfield
Thickness from
Baseline to 16 Weeks
(25th, 75th quartiles)
Median Change in
Visual Acuity from
Baseline to 16 Weeks
(25th, 75th 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)
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
Protocol
Median Change in OCT
Central Subfield
Thickness from
Baseline to 16 Weeks
(25th, 75th quartiles)
Median Change in
Visual Acuity from
Baseline to 16 Weeks
(25th, 75th 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)
35
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
o Why? Only 1 injection? Younger cohort? Lower enthusiasm to
operate on cataracts in this advance DR cohort? Other factors?
36
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
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
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
• 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
41
Recruitment
Follow-Up
Step Changes of Improvement/Worsening in
Diabetic Retinopathy by Baseline Severity
Sham
+ Prompt
Laser
Ranibizumab
+ Prompt
Laser or
Deferred Laser
Triamcinolone
+ Prompt
Laser
N = 150
N = 182
N = 80
Improved by ≥2 levels
4%
25%
25%
Worsened by ≥2 levels
7%
3%
3%
P = .08
P = .17
Change from Baseline to 1-Year
Visit*
Baseline Severity:
Moderately Severe NPDR or Better
P value for comparison with
Sham
*Photos
were missing or ungradeable for 61 eyes in the sham + prompt laser group, 72
eyes
in the ranibizumab
NPDR = nonproliferative
diabetic retinopathy.groups, and 33 eyes in the triamcinolone + prompt laser
Step Changes of Improvement/Worsening in
Diabetic Retinopathy by Baseline Severity
Sham
+ Prompt
Laser
Ranibizumab
+ Prompt
Laser or
Deferred Laser
Triamcinolone
+ Prompt
Laser
N = 150
N = 182
N = 80
Improved by ≥2 levels
4%
25%
25%
Worsened by ≥2 levels
7%
3%
3%
P = .08
P = .17
Change from Baseline to 1-Year
Visit*
Baseline Severity:
Moderately Severe NPDR or Better
P value for comparison with
Sham
Baseline Severity:
Severe NPDR or Worse
N = 83
N = 121
N = 70
Improved by ≥2 levels
19%
28%
13%
Worsened by ≥2 levels
8%
1%
3%
P = .03
P = .17
P value for comparison with
Sham
*Photos
were missing or ungradeable for 61 eyes in the sham + prompt laser group, 72
eyes
in the ranibizumab
NPDR = nonproliferative
diabetic retinopathy.groups, and 33 eyes in the triamcinolone + prompt laser
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 noninferior 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
4
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
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
48
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
Years
4
5
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
Years
4
5
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
Years
4
5
Risk of Visual Acuity 5/200 or Worse
Eyes With Proliferative Retinopathy
Event
Rate
40%
DRS
Untreated Eye
30%
20%
10%
ETDRS
0%
0
1
2
3
Years
4
Eyes
Patients
5