the diabetic retinopathy clinical research network comparison of visual and oct outcomes in eyes...

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The Diabetic Retinopathy Clinical Research Network

The Diabetic Retinopathy Clinical Research Network

Comparison of Visual and OCT Outcomes in Eyes with and without Prior Vitrectomy Receiving Anti-Vascular Endothelial Growth Factor Treatment in a Randomized Trial Evaluating Ranibizumab Prompt

or Deferred Laser for Diabetic Macular Edema

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BackgroundBackground Results from DRCR Network showed intravitreous ranibizumab

with prompt or deferred laser is more effective than prompt laser alone through at least 2 years for the treatment of center-involved DME, and the vision benefits attained at year 1 appear to be sustained thru at least 3 years of follow-up

It has been suggested that the duration of action of anti-VEGF agents in eyes with prior vitrectomy would be shorter compared with eyes without prior vitrectomy due to more rapid drug clearance

Lack of supporting data that confirms this hypothesis in a clinical setting, with the exception of 2 small and short term series of DME eyes treated with bevacizumab*†

1⃰Kondo M, Ito Y, Terasaki H. Intravitreal Bevacizumab (Avastin) for Treatment of Persistent Macular Edema in Vitrectomized Eyes. RETINAL CASES & BRIEF REPORTS 1:195–197, 2007

† Yanyali A, Aytug B, Horozoglu F, et al. Bevacizumab (Avastin) for Diabetic Macular Edema in Previously Vitrectomized Eyes. Am J Ophthalmol 2007;144:124–126.

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Primary ObjectivePrimary Objective

To compare

functional and anatomic outcomes

in eyes treated with ranibizumab,

with or without prior vitrectomy,

from the

Laser-Ranibizumab-Triamcinolone (LRT) Trial for Diabetic Macular Edema (Protocol I) within the

DRCR Network

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MethodsMethods Exploratory analysis of study eyes with and

without vitrectomy prior to enrollment assigned to intravitreous ranibizumab with prompt or deferred laser.

Visual acuity (VA), OCT central subfield thickness (CST), OCT volume and the number of injections from baseline thru 3 years* evaluated by pre-enrollment vitrectomy status.

Follow-up data censored from day of vitrectomy for eyes undergoing initial vitrectomy during study follow-up

*156 weeks

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ResultsResults

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Baseline CharacteristicsBaseline CharacteristicsBaseline characteristics were balanced between vitrectomy status groups with respect to subject-level demographic, medical history, and diabetes-related factors, including:

• age• diabetes type• pre-existing cardiovascular conditions • HbA1c

However, imbalances were present for a number of eye-level factors related to DR and DME severity and prior treatment

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Baseline CharacteristicsBaseline CharacteristicsOcular Characteristics Vitrectomy Status

Yes(N = 25, 7%)

No (N = 335, 93%)

Visual Acuity

Mean letter score (Snellen Equivalent)

59 (20/63)

63 (20/63)

OCT CSF Thickness (Stratus)

Mean (25th, 75th percentile) 368 (290, 471) 408 (311, 484)

OCT Volume (mm3)

Mean (25th, 75th percentile) 8.3 (7.5, 8.8) 8.9 (7.5, 9.7)

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Baseline CharacteristicsBaseline Characteristics

Ocular Characteristics Vitrectomy Status

Yes(N = 25)

No (N = 336)

Prior PRP 64% 20%

Prior DME Treatment 96% 61%Prior Treatment with Anti-VEGF for DME

20% 12%

Lens Status Phakic 36% 72% Pseudophakic 64% 28%

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Baseline CharacteristicsBaseline CharacteristicsOcular Characteristics Vitrectomy Status

Yes(N = 25)

No (N = 336)

DR Severity on clinical exam

None/Microaneurysms only 8% 3%

Mild/moderate NPDR 16% 55%

Severe NPDR 4% 21%

PDR and/or prior scatter 72% 21%

Randomized treatment assignment

Ranibizumab + prompt laser 64% 49%

Ranibizumab + deferred laser 36% 51%

7 variables identified as imbalanced, which may affect outcomes: VA, OCT CSF thickness and volume, Prior PRP, Prior DME treatment,Prior anti-VEGF for DME, Lens status, DR severity, and randomized

assignment to specific ranibizumab group.

0 4 8 12 16 20 24 28 32 36 40 44 48 52 104 1560123456789

101112

No VitrectomyVitrectomy

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Adjusted Mean Change in Visual Acuity by Pre-Enrollment Vitrectomy Status

Adjusted Mean Change in Visual Acuity by Pre-Enrollment Vitrectomy Status

Means were adjusted for 6 of 7 imbalanced baseline covariates (exception was OCT volume).No difference was identified between groups 10

N = 306

N = 19

N = 24

N = 24

N = 20

N = 255N = 312

N = 283

Adjusted Mean Change in CSF Thickness by Pre-Enrollment Vitrectomy Status

Adjusted Mean Change in CSF Thickness by Pre-Enrollment Vitrectomy Status

-180

-160

-140

-120

-100

-80

-60

-40

-20

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60No VitrectomyVitrectomy

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0 4 8 12 16 20 24 28 32 36 40 44 48 52 104 156

Means were adjusted for imbalanced baseline covariates.

N = 19

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P = 0.009

P = 0.035

N = 23

P =0.24

N = 24

P =0.33 P =0.11

N = 19

N = 305 N = 310

N = 278 N = 251

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Adjusted Mean Differences Between Non-vitrectomized and Vitrectomized Eyes

Adjusted Mean Differences Between Non-vitrectomized and Vitrectomized Eyes

Visit - Week 52 Week Visit 104 Week Visit 156 Week Visit

Mean Change in Visual Acuity Letter Score

Vitrectomized 8.9 10.8 7.6

Non-vitrectomized 9.0 8.9 8.7

Difference (99%CIs) -0.1 (-5.1, 4.8) 2.0 (-3.0, 6.9) -1.1 (-6.3, 4.1)

Mean Change in Central Subfield Thickness (μm)

Vitrectomized -115 -131 -124

Non-vitrectomized -138 -150 -157

Difference (99%CIs) 22 (-27, 71) 18 (-30, 67) 33 (-19, 85)

Mean Change in OCT Volume (mm3)

Vitrectomized -1.3 -1.6 -1.6

Non-vitrectomized -1.5 -1.6 -1.7

Difference (99%CIs) 0.2 (-0.4 0.8) 0.0 (-0.5, 0.6) -0.1 (-0.5, +0.7)

• Mean differences in VA and CSF were adjusted for imbalanced baseline covariates.• OCT CST and volume converted to Zeiss Stratus equivalent values.

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TreatmentTreatment

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Number of anti-VEGF Injections During Follow-up Visits by Vitrectomy Status


Vitrectomy StatusMedian (25th, 75th percentile)

N Vitrectomized N Non-vitrectomized

Baseline to 24 week visit 25 6 (5, 6) 317 6 (5, 6)

>24 to 52 week visit 24 5 (2, 6) 312 3 (1, 5)

>52 to 104 week visit 24 2 (0, 8) 284 2 (0, 5)

>104 to 156 week visit 20 1 (0, 2) 258 1 (0, 4)

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Vitrectomy StatusMedian (25th, 75th percentile)

N Vitrectomized N Non-vitrectomized


>24 to 52 week visit 24 5 (2, 6) 312 3 (1, 5)

>52 to 104 week visit 24 2 (0, 8) 284 2 (0, 5)

>104 to 156 week visit 20 1 (0, 2) 258 1 (0, 4)


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Laser Treatment by Pre-Enrollment Vitrectomy Status and Treatment Arm

Laser Treatment by Pre-Enrollment Vitrectomy Status and Treatment Arm

Treatment Ranibizumab + Laser Group

Ranibizumab + Deferred Laser Group

Follow-Up Time

Vitrectomy Status

Yes No Yes No

Baseline up to 52 weeks N = 15 N = 150 N = 9 N = 162

Median (q1, q3) 2 (1, 3) 2 (1, 3) 1 (0, 1) 0 (0, 1)

Baseline up to 156 weeks N = 13 N = 126 N = 7 N = 132

Median (q1, q3) 2 (1, 3) 3 (2, 4) 1 (1, 2) 0 (0, 2)

Ranibizumab + Deferred laser:

Vitrectomy Gp: 1 of 7 eyes (14%) no laserNon-vitrectomy Gp: 75 of 132 eyes (57%) no laser; p=0.05

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Limitations of this AnalysisLimitations of this Analysis Post-hoc nature of study Limited number of cases with prior vitrectomy Potential differences (confounding factors)

other than vitrectomy between the eyes in the vitrectomy and no prior vitrectomy groups that might account for differences noted

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ConclusionsConclusions Among the small group of eyes with vitrectomy prior to

enrollment, change in VA and OCT thickness from baseline and number of injections and lasers, appears similar to eyes without prior vitrectomy, after adjustment for baseline differences in ocular and prior treatment characteristics*• Note: during the 1st year of treatment, eyes without prior

vitrectomy appeared to have more rapid reduction in retinal thickness.

This exploratory analysis showed little evidence that eyes similar to those enrolled and treated in this trial with DME and a history of prior vitrectomy would have a clinically different result, particularly in the long run, from those without vitrectomy.

* VA, OCT CSF thickness (and volume for volume outcome), DR severity, Prior PRP, Prior DME treatment, Prior anti-VEGF for DME, lens status, and randomized treatment assignment

the diabetic retinopathy clinical research network comparison of visual and oct outcomes in eyes...

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