Retinal Vein Occlusion Studies

Dr. Riyad Banayot

Prevalence Retinal vein occlusions (RVOs) are the 2nd most common retinal vascular diseases after diabetic retinopathy.

The Beaver Dam Study reported a prevalence of 0.1% in patients older than 43 years.

A cross-sectional study from 6 US communities reported that the prevalence of CRVO was 0.2%. (the prevalence was similar across different ethnic and racial groups).

The Blue Mountains Eye Study, the 10-year cumulative incidence of CRVO in a population older than 48 years was 0.4%.

The Singapore Malay Eye Study reported a 0.2% prevalence of CRVO in the Malay population 40 to 80 years old.

The Beijing Eye Study reported that the prevalence of CRVO in a Chinese population of people 40 years and older was 0.1%.(No racial or gender predilection for the disease is apparent).

Associated systemic factors

DiabetesHypertensionHyperlipidaemiaHyperhomocysteinaemia Blood coagulation disorders:

high plasma viscosity such as due to leukaemia, myeloma, Waldenstrom’s macroglobulinaemia, myelofibrosis, changes in protein C pathway, Factor V Leiden.

Systemic inflammatory disorders(Behçets disease, polyarteritis nodosa, sarcoidoisis, Wegener’s

Granulomatosis and Goodpasture’s Syndrome) Glaucoma Shorter axial length Retrobulbar external compression

CRVODisc edemaIncreased dilatation

and tortuosity of all retinal veins

Widespread deep and superficial hemorrhages

Cotton wool spotsRetinal edemaCapillary non-

perfusion in all four quadrants of the retina

HRVO & BRVO

Complications

Classical TreatmentBranch Vein Occlusion Study, 1984, showed

that macular photocoagulation for the treatment of macular edema was superior in improving visual acuity compared with observation.

Central Vein Occlusion Study, 1995, showed that grid laser treatment of macular edema was of no visual benefit despite the elimination of macular edema in treated eyes. Observation for macular edema secondary to CRVO was the standard of care set by this study.

Pharmacologic Rx options for Macular edema

Dexamethasoneintravitreal implant (Ozurdex)

Ranibizumab(Lucentis)

Aflibercept (Eylea)

Bevacizumab (Avastin)

CRVO FDA FDA FDA Off labelBRVO FDA FDA Off label

RVO studiesSCORE-C/B 2009 IV Triamcinolone Vs.

Observe/GridGENEVA-C/B 2010 evaluate IV Dexamethasone

extended to 1 yearSHASTA-C/B 2014 evaluate IV DexamethasoneCRUISE-C 2010 evaluate IV Ranibizumab

extension HORIZONBRAVO-B 2010 evaluate IV Ranibizumab

extension RETAINCOPERNICUS-C 2014 evaluate IV AfliberceptGALILEO-C 2014 evaluate IV AfliberceptVIBRANT-B 2013 evaluate IV Aflibercept

SCORE study 2009

Compared the use of 1-mg, 4-mg intravitreal triamcinolone (Trivaris*) to standard care:

Observation for CRVO Grid laser for BRVO

• unpreserved triamcinolone • Triesence

Results: SCORE-BRVO

Trivaris 1mg Trivaris 4mg Grid LaserYear 1VA gain ≥ 3 lines

26% 27% 29%

Year 2 & 3VA

Sustained Sustained Sustained

Patients who were randomized to grid laser underwent a mean 1.5 treatments in year 1, and those who received IVTA had an average of 2 injections

• The rates of cataract formation and IOP elevation were higher in the steroid groups

• The recommendation was that laser remain the standard of care for BRVO

Results: SCORE-CRVO

Trivaris 1mg Trivaris 4mg ObservationYear 1VA gain ≥ 3 lines

27% 26% 7%

Year 2VA

Sustained Sustained

Patients received an average of 2 injections of IVTA over the course of 1 year

GENEVA study 2010

Evaluated dexamethasone intravitreal dexamethasone implant (Ozurdex) for the treatment of macular edema 2ry to BRVO or CRVO

Entry criteria:VA: 20/50 to 20/200CMT ≥300 μm

0.7 mg Dexamethasone

0.35 mg Dexamethasone

Sham

Single treatment

Single treatment

Single treatment

Results: GENEVA study3 month FU

0.7 mg Ozurdex

0.35 mg Ozurdex

Sham

VA improvement ≥15 letters

22% 23% 13%

CMT improved by

208 ±201 μm

177 ±197 μm

85 ±173 μm

After 3 months, there were significant improvements in visual acuityPatients with greater than 90 days’ duration of macular edema associated with BRVO observed a significantly greater response rate

Results: GENEVA study 6 month FU

0.7 mg Ozurdex

0.35 mg Ozurdex

Sham

VA improvement 15 or more letters

22% 19% 18%

CMT improved by

119 ±203 μm

123 ±212 μm

119 ±188 μm

Changes in VA nor CMT for treatment groups were NOT significant when compared with the sham group at the 6-month interval

Extension of GENEVA study

After 6 months, study was extended to 12 monthsPatients received the open-label 0.7 mg

Dexamethasone intravitreal implantCriteria:

VA: <84 ETDRS letters or CMT: >250 um

12 month 0.7 mg Ozurdex

Sham

BCVA improvement 32% 30%

Results: Extension of GENEVA study

12 month 0.7 mg Ozurdex

Sham

BCVA improvement 32% 30% 12 month X2 0.7 mg

OzurdexSham

Cataract 29.8% 5.7% 12 month 0.7 mg OzurdexIOP increase ≥10 mm Hg (1st injection)

12.6%

IOP increase ≥10 mm Hg (2nd injection)

15.4%

SHASTA Study 2014

The effects of multiple dexamethasone implants for macular edema secondary to CRVO or BRVO

Patients received a mean 3.2 dexamethasone implants with mean injection interval between implants was 5.6 months

After 6 implants BRVO CRVOBCVA gain ≥2 lines 59.7% 66.7%CMT significant

reductionsignificant reduction

IOP increase ≥10 mm Hg

32.6%Medical treatment for high IOP

29.1%

Surgical treatment for high IOP 1.7%Laser treatment for high IOP 1.4%

CRUISE study 2010

12-month clinical trialEvaluated the efficacy and safety of anti-VEGF

injections in the treatment of macular edema secondary to CRVO

Criteria:visual acuity of 20/40 to 20/320CMT≥ 250 μm

Injections0.3 mg ranibizumab

0.5 mg ranibizumab

Observation

Monthly for 6 M Monthly for 6 M Monthly for 6 M“as needed” basis from months 6-12

“as needed” basis from months 6-12

0.5 mg ranibizumab, followed by “as needed” basis

Results: CRUISE study initial effects of ranibizumab therapy within 7days after the first

injections

6 month FU

0.3 mg ranibizum

ab

0.5 mg ranibizum

ab

Observation

VA improvement ≥3 lines

46.2% 47.7% 16.9%

Letters from baseline BCVA

12.7 14.9 0.8

CMT improved by

433.7 ±51.2 μm

452.3 ±44.7 μm

167.7 ±53.7 μm

These improvements were maintained in both treated groups at 12 months

HORIZON studyextension of CRUISE study

HORIZON extension trial, patients continue to receive 0.5mg ranibizumab on a PRN basis

FU on a mandatory quarterly basis for the next year A total of 151 patients with CRVO received ranibizumab

therapy and the mean number of injections was 3.9 (range 0 – 12).

Ranibizumab 0.5mg

SHAM

VA improvement from CRUISE baseline

- 4.1

Letters gained from CRUISE baseline

12 7.6

BRAVO study 2010

12-month clinical trialEvaluated the efficacy and safety of anti-VEGF

injections in the treatment of macular edema secondary to BRVO

Injections0.3 mg ranibizumab

0.5 mg ranibizumab

Sham

Monthly for 6 M Monthly for 6 M Monthly for 6 M“as needed” basis from months 6-12

“as needed” basis from months 6-12

0.5 mg ranibizumab, followed by “as needed” basis

subjects were eligible to receive rescue laser treatment during the clinical trial

Results: BRAVO study6 month FU

0.3 mg ranibizum

ab

0.5 mg ranibizum

ab

Sham

VA improvement ≥3 lines

55.2% 61.1% 28.8%

Letters from baseline BCVA

16.6 18.3 7.3

CMT improved by

337.3 ±38.3 μm

345.2 ±41.2 μm

157.7 ±38.6 μmEffects were not permanent and the patients might require several

re-injections

RETAIN studyextension of CRUISE study

The RETAIN study was an extension study for patients who completed the HORIZON study.

Only 34 patients from the BRAVO study were enrolled in the RETAIN study. On average, patients had a follow-up of 4 years.

Patients were followed monthly during the first year of the study and at least every 3 months during the second year of the study.

Reinjections were performed if intraretinal fluid was identified. Results demonstrate the excellent long-term outcomes of eyes

with macular edema secondary to BRVO.

RanibizumabResolution of macular edema

44%

VA improvement ≥3 lines 53%BCVA of 6/12 or better 80%

COPERNICUS study 2014

Evaluating the efficacy of aflibercept in CRVOEntry criteria:

VA: 20/40 to 20/320 CMT >250 μm

2 mg aflibercept ShamMonthly for 6 M Monthly for 6 M“as needed” basis from months 6-12

Allowed to receive afliberceptafter week 24

Results: COPERNICUS study

6 month FU 2 mg aflibercept ShamVA improvement ≥15 letters

57.9% 12.3%

CMT improved by

457.2 μm 144.8 μm

Benefits were maintained at 52 weeks

GALILEO study 2014

Evaluating the efficacy of aflibercept in CRVOEntry criteria:

VA: 20/40 to 20/320 CMT >250 μm

2 mg aflibercept ShamMonthly for 6 M Monthly for 6 M“as needed” basis from months 6-12

“as needed” basis from months 6-12

Results: GALILEO study

6 month FU 2 mg aflibercept ShamVA improvement ≥15 letters

60% 22%

CMT improved by

448.6 μm 169.3 μm

Benefits were maintained at 52 weeks

VIBRANT Study 2013

Double-masked, randomized, active-controlled study of 183 patients with macular edema following BRVO

Treatment:2 mg intravitreal aflibercept every 4 weeks OR laser treatment, up to week 24

Week 24 2 mg aflibercept

Laser

BCVA improvement ≥15 letters

53% 27%

RVO studies   Recommendation

SCORE-C/B IV Triamcinolone Vs. Grid/Observation

Laser remain the standard of care for BRVO

    IV Beneficial for CRVOGENEVA-C/B evaluate IV

Dexamethasone3M: Changes significant6M: Changes NOT significant

extension   12M: Changes NOT significantCataract 30%, IOP 15%

SHASTA-C/B evaluate IV Dexamethasone

Changes significantIOP 33%

CRUISE-C evaluate IV Ranibizumab VA, letters, CMT improvement

HORIZON   Changes NOT significantBRAVO-B evaluate IV

Ranibizumabimprovement NOT permanent need re-inject

RETAIN   improved CMT & VACOPERNICUS-C evaluate IV Aflibercept improvement maintainedGALLILEO-C evaluate IV Aflibercept improvement maintainedVIBRANS-B evaluate IV Aflibercept improvement better with IV vs.

laser

Summary