rop – emerging therapies march 2011
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Dr Kathryn McCreeryMarch 2011
RVEEH
An International Committee for the Classification of Retinopathy of Prematurity, Arch Ophthalmol 2005;123:991-999.
Stage 1 ROP with demarcation line
An International Committee for the Classification of Retinopathy of Prematurity, Arch Ophthalmol 2005;123:991-999.
Stage 2 ROP at the junction between vascularized and avascular retina
ICROP – Staging
Level of abnormal vascular response observed
An International Committee for the Classification of Retinopathy of Prematurity, Arch Ophthalmol 2005;123:991-999.
Mild to severe stage 3 ROP
Stage 4. Subtotal retinal detachment 4a. Extrafoveal 4b. Retinal detachment involving fovea Stage 5. Total retinal detachment
Funnel: Anterior Posterior Open Open Narrow Narrow Open Narrow Narrow
An International Committee for the Classification of Retinopathy of Prematurity, Arch Ophthalmol 2005;123:991-999.
Stage 5 retinopathy of prematurity
All infants born in 26 centers Oct 2000 – Sept 2002
BW <1250g Survived 28 days First exam at @ 6 weeks Weekly exams Zone 1 or Zone 2 stage 2
Zone 1, any stage < threshold Zone 2, stage 2, + plus Zone 2 , stage 3, - plus Zone 2, stage 3, + plus < threshold
Data entered to risk programme based on natural history data from Cryo ROP
Stratified into high risk and low risk prethreshold
Risk > 15% - second masked confirming exam Randomized to early or conventional treatment
at threshold (within 48hrs)
401 Randomized
317 Bilateral Cases44 Asymmetric Cases
(Treated)40 Asymmetric Cases
( Controls)
9 month grating (Teller) VA by masked tester Also a 6 and 9 month structural exam Amblyopia /refractive error treated between 6
and 9 month exam
Favorable Normal 3.70
cycles/degree Below normal 1.85 –
3.70 cycles/degree
Unfavorable Poor <1.8 cycles but
measurable Blind (NLP/LP/LV)
Posterior fold involving macula RD involving macula Retrolental tissue Any eye that had vitrectomy or scleral buckle
96% of those who survived Unfavorable outcome reduced form 19.5% to
14.5% with early intervention P < 0.01
Early treatment reduced risk of unfavorable structural outcome
15.9% (conventional) to 9.1%(early) P < 0.001
“Results from 31 infants with bilateral ROP in whom there were discordant outcomes in the 2 eyes provide even stronger evidence of beneficial effect of treatment at high risk prethreshold ( p = .007)”
Overall 37 of 317 (12%) of high risk prethreshold ROP had an unfavourable outcome in both eyes
Mean BW 703 gms Mean GA 25wks Zone 1 eyes accounted for 40% of those
randomized Greatest benefit in Zone 1, stage 3 +/- plus 30.8% vs. 53.8% unfavorable
Youngest infant treated early was 31weeks PMA
Youngest infant treated conventionally was 32 weeks
Average age at treatment 35 weeks prethreshold and 37 weeks at threshold
Only one eye had cryo 11-14% required retreatment
Cryo ROP 6% required treatment ETROP 9% will need treatment
Systemic complications higher in early treatment group (apnea, bradycardia, reintubation)
Ocular complications similar
Zone 1, any stage, + plus Zone 1, stage 3, - plus Zone 2, stage 2 or 3, + plus
An International Committee for the Classification of Retinopathy of Prematurity, Arch Ophthalmol 2005;123:991-999.
Examples of aggressive posterior retinopathy of prematurity (AP-ROP)
Bevacizumab Eliminates the Angiogenic Threat of ROP
Pathogenesis and Therapy of Retinopathy of Prematurity (ROP).
Mintz-Hittner HA et al. N Engl J Med 2011;364:603-615
1500 gm and 30 wks PCA March 2008 – August 2010 Stage 3+ ROP Zone 1 or Posterior Zone 2 Retcam photos Confirming evaluation of photos by second
ophthalmologist Both eyes randomized to injection or laser
0.625mg bevacizumab in 0.025ml Indirect laser
Enrollment, Randomization, and Follow-up of the 150 Study Infants.
Mintz-Hittner HA et al. N Engl J Med 2011;364:603-615
Photos at 1 week, 1 month and 54 weeks Photos sent to BEAT ROP reading centre Photos cropped to remove peripheral retina to
assess structural outcome If at week one there were skip areas in the laser
group they received supplemental laser which were not considered to be recurrences
Significantly less for injection (6%) vs laser (26%) Recurrence significantly higher with laser than
injection in Zone 1 disease 42% vs 6% Only 2 of 70 eyes injected developed RD ( both
unilateral)
Risk Factors and Other Characteristics of Infants with Zone I Retinopathy of Prematurity (ROP) or Zone II Posterior ROP, According to Treatment Group.
Mintz-Hittner HA et al. N Engl J Med 2011;364:603-615
Ocular Outcomes in the 143 Survivors at 54 Weeks' Postmenstrual Age.
Mintz-Hittner HA et al. N Engl J Med 2011;364:603-615
Characteristics of Infants Who Died.
Mintz-Hittner HA et al. N Engl J Med 2011;364:603-615
Fundus Photographs and Fluorescein Angiograms of Retinas in Study Infants with Stage 3+ Retinopathy of Prematurity in Zone I, before and after Treatment.
Mintz-Hittner HA et al. N Engl J Med 2011;364:603-615
Study Overview
• In this trial, one intravitreal injection of bevacizumab was administered to treat retinopathy of prematurity of stage 3+.
• Bevacizumab was more effective than conventional laser therapy in preventing recurrence of neovascularization in infants with zone I but not zone II posterior retinopathy.
Conclusions
• Intravitreal bevacizumab monotherapy, as compared with conventional laser therapy, in infants with stage 3+ retinopathy of prematurity showed a significant benefit for zone I but not zone II disease.
• Development of peripheral retinal vessels continued after treatment with intravitreal bevacizumab, but conventional laser therapy led to permanent destruction of the peripheral retina.
• This trial was too small to assess safety.
Avoidance of GA’s Beneficial in Zone 1
eyes Sparing of peripheral
field Normal retinal
vascularization
What happened after failure not clear
Endophthalmitis risk Systemic absorption
and risks Recurrence occurs
later 19 vs 6 wks in zone 1 disease
Visual outcomes?
Monotherapy Initial therapy followed by salvage laser Laser failures Role of repeat injection Biggest concern is systemic safety
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