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Up to Date on Treatment of Myopic CNV
F Bandello, MD, FEBO, & M Battaglia Parodi, MD
Department of Ophthalmology
University Vita-Salute
San Raffaele Scientific Institute
Milan, Italy
Financial Disclosures
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Advisory Board Member for:
Alcon
Alimera
Allergan
Bausch and Lomb
Bayer
Boehringer-Ingelheim Pharmaceuticals
Genentech
Hoffmann-La Roche
Novagali Pharma
Novartis
Pfizer
Sanofi-Aventis
Santen
Sifi
Sooft
Thea
Thrombogenics
Myopic Eye
• Physiologic Myopia
• Spherical refractive error not exceeding -6 Dioptres
• Curvature Myopia
• Index Myopia
• Axial Myopia
• Pathological Myopia
• Spherical refractive errors of at least -6.0 D, with eye
axial length exceeding a certain threshold (typically
25.50 or 26.50 mm)
Most Important Retinal Diseases Related to
Myopic Eye
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Retinal Detachment
Peripheral Retinal Degenerations
Retinal Tears
Retinoschisis
Myopia-Associated Dystrophies
Myopia-Associated Inflammatory Conditions
Myopic Maculopathies with CNV
Retinal Disorders Related to Myopia
• Prevalence of myopic retinopathy in general population
0.9-3.1%
• Prevalence higher in Asian populations up to almost 2.5
times higher
• Non-linear relationship between refraction values and
prevalence of myopic retinopathy
Myopic Fundus Changes
F
A: Tessellated fundus
C: Patchy chorioretinal atrophy
E: Lacquer cracks
B: Diffuse chorioretinal atrophy
D: Macular hemorrhage
F: Choroidal Neovasculariaztion
Tokoro T. Types of fundus changes in the posterior pole. In: Tokoro T Ed. Atlas of posterior fundus changes in
pathologic myopia. Tokyo. Springer-Verlag. 1998:5-22
Myopic Maculopathies
Hayhashi K et al. Long-term pattern of progression of myopic maculopathy. Ophthalmology 2010;117:1595-1611
Myopic CNV
• 5-10% of myopic eyes
• Subfoveal CNV in about 60% of cases & juxtafoveal
CNV in about 30% of cases
• Small size (generally <1 optic DD)
• Minimal subretinal fluid
• Generally no exudates
• Location between NR and RPE
• Progressive VA loss over natural history
Myopic CNV Subtypes
3 main FA patterns identified (51 eyes/49 pts):
• Inactive CNV with no leakage: 3 eyes (5%)
No exudative signs on SD-OCT
• Minimal-leakage CNV: 18 eyes (35%)
Limited exudative signs on SD-OCT
• Profuse-leakage CNV: 30 eyes (59%)
Clear exudative signs on SD-OCT
Battaglia Parodi M, Iacono P, Bandello F. Submitted for publication
Anti-VEGF Therapy for Myopic CNV
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VEGF expression in myopic CNV
Aqueous VEGF reduced after IVB
Effective in halting CNV progression
Variable VA gain
Intravitreal injection well tolerated with no particular
safety issues reported
• Still questions about diagnosis & monitoring
Watanabe D, et al. Retina. 2005
Chan WM, et al. Retina. 2008
Battaglia Parodi M, Iacono P, Bandello F. Dev Ophthalmol. 2010
Management
• Diagnosis & Monitoring:
• Fluorescein angiography gold standard
• Prompt detection of CNV leakage
• Invasive examination
• OCT practical and quick
• Identification of CNV & fluid characteristics
• No precise correlation between FA and OCT
OCT and FA Monitoring
+ OCT
Fluid
+ FA
Leakage
- OCT
No Fluid
- FA
No Leakage
OCT and FA Monitoring
+ OCT
Fluid
- FA
No Leakage
- OCT
No Fluid
+ FA
Leakage
OCT and FA Monitoring
• Comparison of detection of leakage on FA vs detection
of fluid on SD-OCT
• 34 eyes (34 pts) with subfoveal CNV undergoing IVB with PRN
regimen over 24 months of follow-up
• Inter-rater agreement kappa analysis, sensitivity/specificity
BL
1M
2M
3M
4M
5M
6M
7M
8M
9M
10M
11M
12M
Sensitivity
77,4
73,3
69,2
61,5
Specificity
66,7
100
100
95,2
62,5
80
78,5
87,5
85,7
77,8
66,6
66,6
71,4
88,4
100
100
100
92,5
96
100
100
96,3
Kappa value
0,23
0,75
0,73
0,60
0,51
0,87
0,81
0,91
0,74
0,76
0,78
0,78
0,71
Complete Agreement
26
30
30
28
28
33
31
33
31
31
33
33
31
OCT+/FAG-
1
FAG+/OCT-
7
0
0
1
3
0
0
0
2
1
0
0
1
4
4
5
3
1
3
1
1
2
1
1
2
24M
13M
14M
15M
16M
17M
18M
19M
20M
21M
22M
23M
Sensitivity
100
100
100
100
100
100
100
100
100
100
100
100
Specificity
100
100
100
100
100
96
100
100
100
100
87
94,1
Kappa value
1
1
1
1
1
0,92
1
1
1
1
0,54
0,63
Complete Agreement
34
34
34
34
34
33
34
34
34
34
30
32
OCT+/FAG-
0
0
0
0
0
1
0
0
0
0
4
2
FAG+/OCT-
0
0
0
0
0
0
0
0
0
0
0
0
Bandello F, Iacono P, Parodi MB, Da Pozzo S. Ophthalmic Res 2013
OCT and FA Monitoring
• Agreement at baseline 26/34 (Sensitivity: 77.4 - Specificity:
66.7- k value: 0.23)
• FA and OCT agreement in 30-34/34 cases from 5th mos
on, (Sensitivity: 66.6-100 - Specificity: 87-100- k value: 0.54-1)
• Diagnosis Phase:
• Superiority of FA in detecting CNV activity
• In 20% of cases SD-OCT failed to detect IRF/SRF when active
dye leakage was visible on FA
• Monitoring Phase:
• Sensitivity, specificity and the k values show a better
agreement with
a high consensus from 5th to 24th month
• Complete agreement achieved in 9 sessions
Bandello F, Iacono P, Parodi MB, Da Pozzo S. Ophthalmic Res 2013
SD-OCT Signs of Myopic CNV
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CNV (size, location, height)
Intraretinal cysts
Subretinal fluid
Subretinal material
Outer retinal tubulation
ELM irregularity
Choroidal thickness alterations
OCT Features of Active Myopic CNV
• Assessment of OCT alterations in active CNV at
diagnosis and over follow-up after anti-VEGF
• 30 eyes undergoing IVB with PRN regimen
• Active CNV on FA with leakage
ACTIVE CNV
Baseline
Follow-up
Intraretinal Cysts
3%
0%
Intraretinal Cysts & Subretinal Fluid
40%
16%
Subretinal Fluid
46%
75%
ELM Irregularity
100%
100%
Battaglia Parodi M, Iacono P, Bandello F. Retina 2015
OCT Features of Active Myopic CNV
• Assessment of OCT alterations in active CNV at
diagnosis and over follow-up after anti-VEGF
• 30 eyes undergoing IVB with PRN regimen
• Active CNV on FA with leakage
ACTIVE CNV
Baseline
Follow-up
Intraretinal Cysts
3%
0%
Intraretinal Cysts & Subretinal Fluid
40%
16%
Subretinal Fluid
46%
75%
ELM Irregularity
100%
100%
Battaglia Parodi M, Iacono P, Bandello F. Retina 2015
Myopic CNV with Intraretinal Cysts
Myopic CNV with Subretinal Fluid
Myopic CNV with Subretinal Fluid &
Subretinal Material
Subretinal Material
Myopic CNV with ELM Interruption
Baseline
(BCVA 20/40)
1 month post-IVB
(BCVA 20/20)
2 months post-IVB
(BCVA 20/20)
2 week later
(BCVA 20/32)
IVB injection
1 month post-IVB
(BCVA 20/20)
Regular ELM
Irregular ELM
Irregular ELM
Active CNV
Leakage
NS detachment
Same area of FA leakage
Treatment Strategies
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Fixed Regimen
PRN
VA-based Regimen
OCT-based Regimen
Response-based Regimen
REPAIR
 Phase II, open-label, single-arm, multicentre, 12 month study
 Re-treatment decision based on OCT and then on FA
Myopic CNV
11 day screening period
Patient eligible
Baseline (Visit 2, Month 0)
Month 1-12 * individualized
treatment based on a pre-specified
retreatment algorithm
Ranibizumab, 0.5 mg (n= 65)
Monthly PRN* ranibizumab
Interim analysis at Month 61
12 month primary
endpoint analysis
1. Tufail A, et al. Eye 2013;27:709-715
REPAIR Results
Outcome
Ranibizumab 0.5 mg (n = 65)
Month 61
Month 122
Mean ± SD change in BCVA from baseline, letters
12.2 ± 14.6***
13.8 ± 14.0***
Proportion of patients gaining ≥ 10 letters, n (%)
–
33 (50.8)
Proportion of patients gaining ≥ 15 letters, n (%)
23 (36%)
24 (36.9)
Mean ± SD change in central macular thickness
from baseline, μm
–108 ± 109***
–135 ± 134***
2.9 (2.0)
3.6 (3.0)
Mean (median) number of injections
***p < 0.001 vs baseline
Tufail A, et al. Eye 2013
Tufail A, et al. Ophthalmology 2013
RADIANCE
VA vs DISEASE ACTIVITY
Investigator determines eligibility
Randomized 2:2:1, N = 277
0.5 mg ranibizumab
(Group I; VA stabilization*)
(n = 106)
0.5 mg ranibizumab
(Group II; disease activity**)
(n = 116)
vPDT (+ ranibizumab from Month 3#)
(Group III)
(n = 55)
Primary endpoint at Month 3
Non-inferiority assessment (Group II vs Group I) at Month 6
Study completion at Month 12
*Ranibizumab on Day 1 and Month 1, thereafter based on stabilization criterion (no change in BCVA as compared to two preceding
monthly visits)
**Ranibizumab on Day 1 and thereafter based on a disease activity criterion (attributable to intra or subretinal leakage secondary
to PM as assessed by OCT and/or FA)
#Patients randomized to vPDT were allowed to receive vPDT and/or ranibizumab treatment at investigator’s discretion from Month
3 onwards
RADIANCE Results
Ranibizumab treatment resulted in a rapid improvement in BCVA in Groups I and II during the first three
months, which was sustained to Month 12
In the vPDT group, the BCVA gain was less up to Month 3, but a steady increase was observed after switching
to ranibizumab
Mean change (±SE) in BCVA
from baseline (ETDRS letters)
;
Ranibizumab 0.5 mg/vPDT as of Month 3 as per investigators’ discretion
14.4
13.8
12.5
12.1
9.3
1.4
D8
Months
Full analysis set (modified last observation carried forward)
Wolf S, et al. Ophthalmology 2014;121:682–92
RADIANCE Results (2)
Number of ranibizumab injections (Day 1 prior to Month 12)
Safety set*
n1,2
Total1
Mean (SD)1,2
Median1,2
Ranibizumab 0.5 mg
(Group I; VA
stabilization)
Ranibizumab 0.5 mg
(Group II; disease
activity)
vPDT (+ ranibizumab
from Month 3)
(Group III)
105
489
4.6 (2.6)
4.0
116
412
3.5 (2.9)
2.0
38
123**
3.2 (2.5)
2.0
*Two patients randomized to vPDT each received one ranibizumab injection prior to Month 3 and were reported in Group II
for all safety analyses
**vPDT group received ranibiuzmab 0.5 mg/vPDT as of Month 3
Wolf S, et al. Ophthalmology 2014;121:682–92
Treatment Regimen According to First Reponse
to Ranibizumab
Allocation according to response to first injection
•PRN Group if: no leakage, no OCT fluid, no new hemorrhages
•Loading Phase + PRN Group if: leakage on FA, or fluid on OCT, or new
hemorrhages
Subfoveal
CNV
1 IVRI
PRN
Loading Ph
+ PRN
Iacono P. Battaglia Parodi M, Bandello F. Acta Ophthalmol 2015
Results
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0
0,73
0,61*0,60 0,60 0,61 0,62
0,75
0,54*
0,48*0,48*
CMT
LogMAR BCVA
Mean BCVA & CMT
0,47*0,47*
PRN
LOAD+PRN
Month
400
350
300
250
200
150
100
50
0
371
337
282*276* 269*
294*
265*
262*252*241*
228*217*
PRN
LOAD+PRN
Month
MEAN Injection Number @ 18 mos:
• PRN Group: 1.3±0.5 VS LOAD + PRN Group: 4.4±1
Iacono P. Battaglia Parodi M, Bandello F. Acta Ophthalmol 2015
Results
Analyses of Main Patient Characteristics
Baseline Characteristics PRN Group
Loading Phase Group
P value
Number of Patients
15
12
Mean age
57±9.8
68.3±8
0.005
Gender
10 F / 5 M
9F/3M
0.07
Mean BCVA (LogMAR)
0.75±0.28
0.73±0.27
0.85
Mean CMT (µm)
337±73
371±111
0.35
Mean GLD (µm)
1126±387
1784±904
0.017
Symptoms Duration
(days)
8.6±4.4
25.8±11
0.0001
Iacono P. Battaglia Parodi M, Bandello F. Acta Ophthalmol 2015
Prognostic Factors With Anti-VEGF
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Prospective study, 48 pts with sub/juxtafoveal CNV
Ranibizumab/Bevacizumab with PRN regimen
12-month follow-up
Prognostic factors considered:
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Symptoms duration
Age
Refractive error
Baseline BCVA
CMT
CNV area
Hemorrhages
Atrophy
Lacquer cracks
Iacono P. Battaglia Parodi M, Bandello F. Submitted for publication
Results
Univariate Regression analysis
Multivariate Regression Analysis
Regression Coefficient (SE)
0,0052 ( 0,003)
-0,0030 ( 0,010)
0,5435( 0,137)
p
0,0946
0,7607
0,0003
Regression Coefficient (SE)
p
0,5609 (0.129)
0,0001
Baseline CNV Area
Baseline CMT
0,0136 ( 0,055)
0,0008 ( 0,0004)
0,8061
0,0961
-
-
Time between onset
and treatment
0,0104 ( 0,0035)
0,0054
0,0117 (0,003)
0,0006
Atrophy
Haemorrhage
Lacquer cracks
-0,1111 ( 0,0943)
-0,0583 ( 0,094)
-0,0055 ( 0,109)
0,2448
0,5405
0,9598
-
-
0,3444 (0,114)
0,0055
0,3283 (0,081)
0,0007
Age
Refractive Error
Baseline BCVA
Pattern of CNV Fundus
(hyper-FAF with better
prognosis)
Better VA when:
1- Higher baseline VA
2- Reduced time between diagnosis & Tx
3- CNV with hyper-FAF pattern
FAF and Myopic CNV
• 27 patients (27 eyes) with mean age 58.30±15.7
• 14 females and 13 males
• FAF: 17 eyes (63%) hyper-autofluorescent pattern
10 eyes (37%) patchy pattern
Battaglia Parodi M, Iacono P, Bandello F. AJO 2015
FAF and Myopic CNV
• BCVA improved from 0.49 to 0.40 LogMAR
• BCVA varied according to FAF patterns
Total
BCVA Baseline BCVA Final
0.49
0.40
Hyper-FAF 17 eyes (63%)
Patchy-FAF 10 eyes (37%)
0.48*
0.51
0.30*
0.56
* Statistically significant difference
Battaglia Parodi M, Iacono P, Bandello F. AJO 2015
Atrophic Changes After Anti-VEGF in
Myopic CNV
• Atrophic changes 70% at baseline and in 92.5% @ 12 mos
• 55.5% enlargement of pre-existing RPE atrophy
• 26% development of new atrophic areas
• 18.5% no change
• RPE atrophy 1.27mm2 @ baseline and 1.83mm2 @ 12 mos
(p: 0.016)
Baseline FAF
Pattern
Number of
Patients
Baseline Mean Final Mean
Atrophy Area Atrophy Area
(mm2)
(mm2)
Hyper-FAF
17 (63%)
1.33
1.70
Patchy-FAF
10 (37%)
1.16
2.06
Battaglia Parodi M, Iacono P, Bandello F. AJO 2015
Perforating Vessels and…
Lacquer Cracks
Myopic CNV
… 3 months before
linear hyporeflectivity – perforating vessels
3 months later…
linear hyporeflectivity – perforating vessels
Lacquer Cracks
LC and Perforating Scleral Vessel
• Lacquer cracks represent
mechanical breaks in the
Bruch membrane–RPE–
choriocapillaris complex
• Scleral discontinuity due to
interruption by perforating
vessels (‘‘locus minoris
resistentiae’’) may lead to
increased stretch forces
being applied to the Bruch
membrane in eyes with
scleral expansion due to
abnormal axial elongation
*
Perforating Scleral Vessels
• Lacquer cracks represent
mechanical breaks in the
Bruch membrane–RPE–
choriocapillaris complex
• Scleral discontinuity due to
interruption by perforating
vessels (‘‘locus minoris
resistentiae’’) may lead to
increased stretch forces
being applied to the Bruch
membrane in eyes with
scleral expansion due to
abnormal axial elongation
*
Perforating Scleral Vessels
• An alternative mechanical
explanation would be that the
vessel acts as a tether, which
creates a point of fixation that
could concentrate forces of
stretch in the sclera or
transmit forces of eye
movement to the choroid
*
CNV & Perforating Scleral Vessels
• OCT images clearly demonstrated the vessels’ course within
the sclera and confirmed their termination just beneath the CNV
CNV & Perforating Scleral Vessels
Analisi dell'angiografia : Angiography 3x3 mm
AngioPlex - Coroide
OD
OS
Struttura - Coroide
Active CNV
Segmento: 191
Firma del medico
Commenti
Analisi modificata:
18:38
04/04/2016 18:37
Monitorato durante la scansione
SW Ver: 9.0.0.281
Copyright 2015
Carl Zeiss Meditec, Inc
All Rights Reserved
Pagina 1 di 1
Analisi dell'angiografia : Angiography 3x3 mm
AngioPlex - Coroide
OD
OS
Struttura - Coroide
Inactive
CNV
Segmento: 158
Firma del medico
Commenti
Analisi modificata:
05/04/2016 16:37
Monitorato durante la scansione
SW Ver: 9.0.0.281
Copyright 2015
Carl Zeiss Meditec, Inc
All Rights Reserved
Pagina 1 di 1
Analisi dell'angiografia : Angiography 3x3 mm
AngioPlex
AngioPlex--Custom
Retina
OD
OS
Struttura
Struttura--Custom
Retina
Inactive
CNV
Segmento: 122
121
Firma del medico
Commenti
Analisi modificata:
06/04/2016 17:13
13:27
Monitorato durante la scansione
SW Ver: 9.0.0.281
Copyright 2015
Carl Zeiss Meditec, Inc
All Rights Reserved
Pagina 1 di 1
CNV & Perforating Scleral Vessels
• No significant difference of prevalence of perforating vessels
between active and inactive CNV (respectively 73% and 71%;
no potential role of fibrosis)
• The “locus minoris resistentiae” into the sclera due to
perforating vessel in eyes with abnormal axial elongation can
play a role in the genesis of CNV (either with or without LC)
*
CNV & Perforating Scleral Vessels
• Perforating scleral vessels are often present beneath the site
where CNV forms in pathologic myopia
• We hypothesize that scleral expansion at the location of these
perforating vessels may play a role in the formation of CNV
Conclusions
•
FA at diagnosis; OCT during the follow-up
•
Anti-VEGF approach effective in improving and maintaining
VA in patients with myopic CNV (enlargement of retinal
atrophy) (many treatment strategy)
•
Early diagnosis, better baseline BCVA & hyper-FAF pattern of
the CNV strongly associated with better functional
outcomes
•
Perforating vessels associated with lacquer-cracks and CNV