Discontinuing Treatments for Diabetic Retinopathy May Increase Neovascularization

Diabetic Retinopathy (Photo By BSIP/UIG Via Getty Images)
Investigators report that continuous treatment is important to ensure that the benefits are not lost due to recurrent NV activity.”

Discontinuation of either ranibizumab or panretinal laser photocoagulation (PRP) monotherapy may lead to an increase in neovascularization (NV) area and visual acuity loss in patients with proliferative diabetic retinopathy, according to research results published in Acta Ophthalmologica

The PRIDE Study (ClinicalTrials.gov identifier NCT01594281) was a phase 2, 12-month, 1:1:1 randomized, open-label, controlled, multicenter study with an observational follow-up phase comparing ranibizumab vs PRP vs combination therapy in patients with proliferative diabetic retinopathy but without diabetic macular edema. The PRIDE Study took place between 2012 and 2017, and the current study presents the results of the second-year observational follow-up period. 

A total of 106 patients participated in the first interventional phase, from baseline to month 12. Participants were randomly assigned to receive either ranibizumab 0.5 mg (n=35), PRP (n=35), and combination ranibizumab 0.5 mg plus PRP (n=36). Twenty-eight, 20, and 25 patients from each group, respectively, participated in the observational follow-up from month 12 to month 24. 

A total of 74 patients entered the follow-up phase, 67 of whom completed the month 24 visit (25, 19, and 23 in each group, respectively). Baseline characteristics were generally well balanced across groups, excepting mean area of NV, which was higher in the ranibizumab group vs the PRP and combination groups (9.02±14.63 mm2 vs 6.19±12.29 mm2 and 2.71±4.09 mm2). Additionally, there were more active smokers in the combination group — 36% — vs the ranibizumab and PRP groups (14.3% vs 10%).

Throughout the observational follow-up phase, study medication was not provided and patients were treated by investigator discretion. 

During the first year, treatment with ranibizumab monotherapy was associated with significantly greater reductions in NV area from baseline through month 12 compared with PRP; the comparisons between ranibizumab and combination therapy and combination therapy and PRP were nonsignificant. 

During the observational follow-up phase, mean NV area in the ranibizumab group increased, from 3.16±4.30 mm2 to 6.09±10.79 mm2 at months 12 and 18, and to 10.00±17.63 mm2 at month 24. The PRP group experienced a decline in NV area from 5.44±14.55 mm2 to 1.22±1.67 mm2 between months 12 and 18, then increased to 4.05±11.66 mm2 at month 24. 

In the combination group, NV area increased from 1.13±2.78 mm2 to 2.14±4.41 mm2 to 3.26 mm2 at months 12, 18, and 24, respectively. 

LS mean change in NV area from baseline to month 24 was 1.0 mm2 (95% CI, -3.2 to 5.1), -2.2 mm2 (95% CI, -6.9 to 2.5), and -0.6 mm2 (95% CI, -5.2 to 3.9) in each group. Between-group differences were nonsignificant. 

The number of patients who developed new neovascularization elsewhere (NVE) vs baseline in each group was 7, 5, and 6 at month 12, 10, 5, and 10 at month 18, and 10, 8, and 12 at month 12, respectively. 

In the ranibizumab group, 22.2%, 11.1%, and 12% of patients experienced complete regression of NV leakage at each time point; in the PRP group, these numbers were 10%, 21.1%, and 23.5%, and in the combination group they were 20%, 16.7%, and 22.7%, respectively. 

Percental agreement for evidence of NVE on fluorescein angiography was 94.6%, and neovascularization of the disc (NVD) evidence was 100% in terms of grading reproducibility. Median difference between gradings for NVE area was 0.11±1.21 mm2, with a median value of original grading of 0.52±6.62 mm2. For NVD area, median difference was 0.00±0.14 mm2 and median value of original grading was 0.00±0.23 mm2.

During the first year of the study, a significant difference was seen in LS mean best-corrected visual acuity of 5.5 letters between the ranibizumab and PRP groups. There was a nonsignificant difference between the ranibizumab and combination groups, and between the PRP and combination groups. 

During the observational follow-up phase, BCVA in the ranibizumab group decreased from 85.6±7.6 letters at month 12 to 81.9±10.8 letters at month 18, before marginally increasing to 82.4±9.9 letters at month 24. In the PRP group, BCVA also decreased between months 12 and 18, before increasing to 78.7±16.8 letters at 24 months. Patients in the combination group experienced a BCVA increase between months 12 and 18 of 81.4±9.3 letters to 82.5±6.9 letters, and a decline to 78.5±18.3 letters at month 24. 

LS mean change in BCVA in each group was -1.1 letters, -2.0 letters, and -4.2 letters, respectively. Between-group differences were nonsignificant. 

Significant LS mean differences in CST change were seen during the first year in the ranibizumab and PRP groups, and between the ranibizumab and combination groups; the difference between the PRP group and the combination group was nonsignificant. 

During the observational follow-up phase, mean CST in the ranibizumab group increased from months 12 to 18 and month 18 to 24. In the PRP group, mean CST decreased at each time point, and in the combination group, mean CST was relatively steady at months 12 and 18 — 254.5±37.1 µm and 254.9±29.2 µm — before increasing to 265.6±33.4 µm at 24 months. 

At month 12, 0, 7, and 2 patients with macular edema in each group. During the observational follow-up period, 1, 5, and 2 patients developed macular edema at month 18 and 3, 5, and 3 patients had macular edema at month 24. 

No Antiplatelet trialists collaboration events were recorded for any treatment group during the follow-up period. No patients underwent vitrectomy in the ranibizumab or PRP groups, while 2 patients in the combination group required vitrectomy. In terms of ocular severe adverse events, 1, 2, and 4 patients in each group experienced these outcomes. 

Study limitations include the relatively small number of patients in each follow-up group, limiting the generalizability of the results. 

“[O]ur data from the observational second year 12-month follow-up of the PRIDE study indicate that [patients with proliferative diabetic retinopathy] require regular monitoring of disease activity,” according to the researchers. “For patients receiving anti-VEGF therapy, continuous treatment is important to ensure that the benefits are not lost due to recurrent NV activity.” 


Lang GE, Stahl A, Voegeler J, et al. Observational outcomes in proliferative diabetic retinopathy patients following treatment with ranibizumab, panretinal laser photocoagulation or combination therapy — The non-interventional second year follow-up to the PRIDE study. Acta Ophthalmol. Published online June 14, 2021. doi:10.1111/aos.14907