Table 1.
Summary of seminal RCTs of treatment for macular oedema secondary to branch retinal vein occlusion.
| Article and authors | Intervention and regimen | Number of eyes | Study duration or time points of reported outcomes | No of injections or treatments, mean (SD) | Visual outcomes (logMAR letters if not indicated) | Anatomical outcomes (µm) | Safety outcomes | Quality of life outcomes |
|---|---|---|---|---|---|---|---|---|
| Laser photocoagulation | ||||||||
| BVOS (BVOS Group, 1984) [2] | Macular grid laser vs. control |
Total: 78 Laser: 43 Control: 35 |
4 years (mean 3.1 years) | N/A |
36 months Laser: 65% gained ≥2 lines Control: 37% gained ≥2 lines |
N/A | One case of Bruch’s membrane perforation but visual acuity not affected | NR |
| Triamcinolone/laser | ||||||||
| SCORE (Scott et al. [4]) | IVTA 4 mg vs. IVTA 1 mg vs. Laser (identical re-treatment criteria and re-treatment permitted at minimum of 4-month intervals) |
Total: 411 IVTA 4 mg: 138 IVTA 1 mg: 136 Laser: 137 |
12 months (primary end point) 36 months |
12 months IVTA 4 mg: 2.1 IVTA 1 mg: 2.2 Laser: 1.5 |
12 months IVTA 4 mg: +4 IVTA 1 mg: +5.7 Laser: +4.2 36 months: IVTA 4 mg: +8 IVTA 1 mg: +4.4 Laser: +12.9 |
12 months IVTA 4 mg: −170 (median) IVTA 1 mg: −149 (median) Laser: −224 (median) 36 months IVTA 4 mg: −250 (median) IVTA 1 mg: −245 (median) Laser: −312 (median) |
12 months IOP-lowering medication initiation: IVTA 4 mg: 41% IVTA 1 mg: 8% Laser: 2% Glaucoma surgery: 0% all groups Cataract onset/progression: IVTA 4 mg: 35% IVTA 1 mg: 25% Laser: 13% Non-ocular AEs similar among groups |
NR |
| Dexamethasone | ||||||||
| GENEVA (Haller et al. [5, 6]) | IVD 0.7 mg vs. IVD 0.35 mg vs. Sham (all groups allowed IVD 0.7 mg at day 180 based on re-treatment criteria) |
Total: 830 IVD 0.7 mg: 291 IVD 0.35 mg: 260 Sham: 279 |
6 months 12 months (for safety surveillance) |
Received second implant on day 180: IVD 0.7 mg: 85% IVD 0.35 mg: 83.1% Sham: 82% |
Only combined BRVO and CRVO data reported | Only combined BRVO and CRVO data reported | Only combined BRVO and CRVO data reported | NR |
| Ranibizumab | ||||||||
| BRAVO (Campochiaro et al. [8], Brown et al. [9]) | IVR 0.5 mg vs. IVR 0.3 mg (6 monthly injections then PRN) vs. Sham (switched to IVR 0.5 mg after 6 months); rescue laser if eligible beginning month 3 and beginning at month 9 |
Total: 397 IVR 0.5 mg: 131 (123 at 12 months) IVR 0.3 mg: 134 (119 at 12 months) Sham: 132 (114 at 12 months) |
6 months (primary end point) 12 months |
0–6 months: IVR 0.5 mg: 5.7 IVR 0.3 mg: 5.7 Sham: 5.7a 6–12 months: IVR 0.5 mg: 2.7 IVR 0.3 mg: 2.8 Sham/IVR 0.5 mg: 3.6 |
6 months: IVR 0.5 mg: +18.3 IVR 0.3 mg: +16.6 Sham: +7.3 12 months: IVR 0.5 mg: +18.3 IVR 0.3 mg: +16.4 Sham/IVR 0.5 mg: +12.1 (p < 0.01 for each IVR group vs. control/IVR 0.5 mg) |
6 months: IVR 0.5 mg: −345.2 IVR 0.3 mg: −337.3 Sham: −157.7 12 months: IVR 0.5 mg: −347.4 IVR 0.3 mg: −313.6 Sham/IVR 0.5 mg: −273.7 (p < 0.05 sham/IVR 0.5 mg vs. IVR 0.5 mg). |
12 months: most frequent ocular AEs Cataract IVR 0.5 mg: 6.2% IVR 0.3 mg: 4.5% Sham (0–6 months): 3.1% Sham/IVR 0.5 mg (6–12 months): 2.6% Vitreous haemorrhage IVR 0.5 mg: 1.5% IVR 0.3 mg: 5.2% Sham (0–6 months): 4.6% Sham/IVR 0.5 mg (6–12 months): 0.9% SAE (non-ocular)b IVR 0.5 mg: 4.6% IVR 0.3 mg: 4.5% Sham (0–6 months): 0.8% Sham/IVR 0.5 mg (6–12 months): 1.7% |
NEI VFQ-25 total score: 6 months: IVR 0.5 mg: +10.4 IVR 0.3 mg: +9.3 Control: +5.4 12 months: IVR 0.5 mg: +10.2 IVR 0.3 mg: +9 Sham/IVR 0.5 mg: +7.4 |
| HORIZON (Heier et al. [10]) | IVR 0.5 mg PRNc (extension trial of BRAVO and Central Retinal Vein Occlusion Study: Evaluation of Efficacy and Safety (CRUISE) trials) | 304 enroled from BRAVO, 205 completed 12 months of HORIZON | Mean 14 months |
Day 1-month 11: IVR 0.5 mg: 2.1 IVR 0.3/IVR 0.5 mg: 2.4 Sham/IVR 0.5 mg: 2 |
12 months Compared with HORIZON baseline: IVR 0.5 mg: −0.7 IVR 0.3/IVR 0.5 mg: −2.3 Sham/IVR 0.5 mg: +0.9 Compared with BRAVO baseline: IVR 0.5 mg: +17.5 IVR 0.3/IVR 0.5 mg: +14.9 Sham/IVR 0.5 mg: +15.6 |
Compared with HORIZON baseline: IVR 0.5 mg: +35.3 IVR 0.3/IVR 0.5 mg: +6.3 Sham/IVR 0.5 mg: +3.7 Compared with BRAVO baseline: IVR 0.5 mg: −330.6 IVR 0.3/IVR 0.5 mg: −291.4 Sham/IVR 0.5 mg: −304.2 |
Over duration of HORIZON: ocular SAE IVR 0.5 mg: 5.8% IVR 0.3/IVR 0.5 mg: 3.9% Sham/IVR 0.5 mg: 2.2% Non-ocular SAEb: IVR 0.5 mg: 5.8% IVR 0.3 mg: 4.9% Sham/IVR 0.5 mg: 1.1% |
NR |
| RETAIN (Campochiaro et al. [11]) | IVR 0.5 mg PRNd (extension of BRAVO and HORIZON) | 34 enroled from BRAVO and HORIZON, 26 completed 2 years | Mean 53.4 months |
1st year: 2.4 2nd year: 1.8 Over 53 months follow-up: 14.8 |
4 years from BRAVO baseline (n = 28, compared with BRAVO baseline): +20.1 |
4 years from BRAVO baseline (n = 28, compared with BRAVO baseline): −277.2e |
Ocular SAE: 4 (none attributable to ranibizumab) Non-ocular SAE: 13 (in 12 patients, no evidence events related to ranibizumab) |
NR |
| SHORE (Campochiaro et al. [90]) |
Day 1-month 7 IVR 0.5 mg monthly for 7 months for all. Month 7–15 If stability criteria met, patients randomised 1:1 to IVR PRN or IVR monthly. If stability criteria not met, patients ‘non-randomised’ and continued IVR monthly. |
Total: 115 (including hemi-retinal vein occlusion) PRN: 48 Monthly: 50 Non-randomised: 17 |
15 months |
IVR Monthly: Only combined BRVO and CRVO data reported Between months 7 and14: IVR PRN: 4 (median) |
Month 7 Monthly: +17.9 PRN: +20.6 Month 15 from baseline Monthly: +18.7 PRN: +23.3 Non-randomised: +15.5 |
Month 15 Monthly: −214.6 PRN: −225.9 Non-randomised: −183.5 |
Ocular SAE: 3% Non-ocular SAE potentially related to systemic VEGF inhibition: 2.5% |
NR |
| Ranibizumab/laser | ||||||||
| BRIGHTER (Tadayoni et al. [12, 13]) |
Day 1–month 6 IVR 0.5 mg PRNf vs. IVR 0.5 mg PRNf + laserg vs. laserg Laser group allowed IVR 0.5 mg PRN from month 6 (Laser/IVRh) |
Total: 455 IVR: 183 IVR + laser: 180 Laser: 92 |
6 months (primary end point) 24 months |
6 months IVR: 4.8 IVR + laser: 4.5 injections + 0.8 laser treatments Laser: 1.2 treatments 24 months IVR: 11.4 IVR + laser:11.3 Laser/IVRh: 8.1 |
6 months IVR: + 14.8 IVR + laser: +14.8 Laser: +6 (p < 0.0001 for IVR+/− laser vs. laser) 24 months IVR: +15.5 IVR + laser: +17.3 Laser/IVRh: +12.1 Laser: +10 |
6 months IVR: −223.3 IVR + laser: −240.1 Laser: −89.8 24 months: IVR: −284.4 IVR + laser: −314.7 Laser/IVRh: −297.4 Laser: −211.6 |
24 months Ocular SAEi IVR: 1.1% IVR + laser: 2.2% Laser: 0 Laser/IVRh: 1.6% Non-ocular SAEi IVR: 15.6% IVR + laser: 15.3% Laser: 12% Laser/IVRh: 14.3% |
NR |
| Aflibercept/laser | ||||||||
| VIBRANT (Campochiaro et al. [14], Clark et al. [15]) |
Week 0–24 IVA 2 mg monthly vs. Macular laser (switched to IVA after week 24)ja Week 28–52 IVA 2 mg 2 monthly (rescue laser available from week 36) vs. Laser/IVA: IVA 3 months loading then 2 monthly |
Total: 183 IVA: 91 Laser: 92 |
24 weeks (primary end point) 52 weeks |
24 weeks IVA: 5.7 Laser: 1.7 treatments |
24 weeks IVA: +17 Laser: +6.9 52 weeks IVA: +17.1 Laser/IVA: +12.2 |
24 weeks IVA: −280.5 Laser: −128 52 weeks IVA: −249.3 Laser/IVA: −283.9 |
52 weeks Ocular SAE IVA 1.1% Non-ocular SAE IVA: 14.3%i Laser (week 0–24): 1.1% APTC-defined event of non-fatal stroke Laser/IVA: 10.9%i; 1.1% APTC-defined event of non-fatal myocardial infarction |
NEI VFQ-25 total score 24 weeks IVA: 7.7 Laser: 6.3 52 weeks IVA 9.4 Laser/IVA: 8.3 |
| Bevacizumab/ranibizumab | ||||||||
| MARVEL (Narayanan et al. [16]) |
IVB 1.25 mg vs. IVR 0.5 mg (both arms single injection at baseline then monthly PRN) |
Total: 75 IVB: 38 IVR: 37 |
6 months |
IVB: 3 IVR: 3.2 |
IVB: +15.6 IVR: +18.1 |
IVB: −201.7 IVR: −177.1 |
Ocular AEk (study eye) IVB: 18.4% IVR: 5.4% Developed systemic hypertensionk IVB: 5.3% IVR: 13.5% |
NR |
| CRAVE (Rajagopal et al. [17]) | IVB 1.25 mg vs. IVR 0.5 mg (both arms 6 monthly injections) |
Total: 98 IVB: 49 IVR: 49 |
6 months | 6 (all patients as per study protocol) |
IVB: +16.5e (0.33 logMAR letters) IVR: +17e (0.34 logMAR letters) |
IVB: −212.6 IVR: −243.8 |
Reported no ocular SAE Reported no myocardial infarction or stroke |
NR |
| Conbercept/ranibizumab | ||||||||
| Li et al. [91] | IVC 0.5 mg vs. IVR 0.5 mg (both arms single injection then monthly PRN)l |
Total: 35 IVC: 18 IVR: 17 |
6 months |
IVC: 2.3 IVR: 2.7 |
IVC: +19.5e IVR: +13e |
IVC: −262.4e IVR: −202.6e |
Reported no serious ocular SAE | NR |
| Ranibizumab/dexamethasone | ||||||||
| COMRADE-B (Hattenbach et al. [19], Feltgen et al. [92]) |
Day 1–month 6 IVR 0.5 mg minimum 3 monthly injections until stable VA then PRN regimen vs. IVD 0.7 mg single implant Month 6–12 (extension) Patients assigned to same treatment groups IVD 0.7 mg eligible for further PRN implants |
Day 1–month 6 Total: 244 IVR:125 IVD:118 Month 6–12 Total: 92 (87 completed) IVR: 52 (51 completed) IVD: 40 (36 completed) |
6 months (primary end point) 12 months |
6 months IVR: 2.9 loading injections and 1.7 PRN re-treatment injections IVD: single implant Month 3 until end of extension study IVR: 4.5 IVD: 0.4 |
6 months IVR: +17.3 IVD: +9.2 Month 12 from baseline IVR: +20 IVD: +12.3 |
6 months IVR: −230.6 IVD: −112.3 Month 12 from baseline IVR: −288.1 IVD: −211.5 |
6 months Ocular SAEs: IVR: 5.6% IVD: 6.8% Non-ocular SAEsi IVR: 5.6% IVD: 6.8% Cataract formation IVR: 0.8% IVD: 3.4% During extension Over 12 months IOP increase (≥21 mmHg) IVR: 13.5% IVD: 59.1% Non-ocular SAE IVR: 3.8% IVD: 7.5% |
NR |
| Bandello et al. [20] | IVR 0.5 mg (monthly until month 5 then PRN month 6–11) vs. IVD 0.7 mg (baseline, month 5 and option of re-treatment at month 10 or 11) |
Total: 307 IVR: 153 IVD: 154 |
12 months |
IVR: 8 IVD: 2.5 |
IVR: +17.4 IVD: +7.4 |
IVR: −252 IVD: −227 |
Increased IOP IVR: 10.7% IVD: 32.7% Ocular hypertension IVR: 0.7% IVD: 5.9% Cataract IVR: 1.3% IVD: 8.5% Hypertension IVR: 6.7% IVD: 3.3% |
NEI VFQ-25 composite score IVR: 7.2 IVD: 2.9 |
All reported figures rounded down to 1 decimal point where applicable.
NEI VFQ-25 The National Eye Institute 25-Item Visual Function Questionnaire, IVTA intravitreal triamcinolone, IVD intravitreal dexamethasone, IVR intravitreal ranibizumab, IVA intravitreal aflibercept, IVB intravitreal bevacizumab, IVC intravitreal conbercept, AE adverse event, SAE serious adverse event, RD retinal detachment, NR not recorded.
aSham injections.
bSAEs potentially related to systemic VEGF inhibition.
cRanibizumab 0.5 mg PRN based on re-treatment criteria, quarterly monitoring visits (or more frequently at the discretion of the investigator) up to month 24 or until 30 days after the Food and Drug Administration (FDA) approval of ranibizumab for treatment of RVO.
dMonitoring visits every month for 12 months then every 3 months or more frequently for another additional 12 months, patients were eligible to receive ranibizumab 0.5 mg if intraretinal fluid was present with foveal involvement.
eConversion of units performed or calculated based on numbers provided in published paper.
fMonthly IVR treatment until study eye’s VA stabilisation for three consecutive monthly assessments, followed by treatment on a PRN regimen until month 6, from month 6 participants received PRN treatment with reduced frequency of monitoring if VA stabilisation achieved.
gLaser treatment to be administered at investigator’s discretion at minimal intervals of 4 months, not to be administered if BCVA ≥ 79 letters or if no macular oedema is present.
hLaser from Day 0 then Ranibizumab 0.5 mg from month 6.
iRegardless of study drug relationship; APTC ATE Antiplatelet Trialists’ Collaboration arterial thrombo-embolic events.
jMacular laser photocoagulation at baseline and, if eligible, rescue laser at week 12, 15 or 20 (≥12 weeks apart from the last laser treatment).
kPercentages calculated based on numbers enroled at baseline, safety set not specified.
lTargeted retinal photocoagulation was administered peripherally when there were areas of non-perfusion measuring >5 disc diameters.