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Original Investigation
April 2018

Association of Changes in Macular Perfusion With Ranibizumab Treatment for Diabetic Macular EdemaA Subanalysis of the RESTORE (Extension) Study

Author Affiliations
  • 1Department of Ophthalmology, Medical University Vienna, Vienna, Austria
  • 2Vienna Reading Center, Medical University Vienna, Vienna, Austria
  • 3Novartis Business Services, Dublin, Ireland
JAMA Ophthalmol. 2018;136(4):315-321. doi:10.1001/jamaophthalmol.2017.6135
Key Points

Question  Do repeated ranibizumab injections worsen macular perfusion in a compromised capillary network, compared with laser monotherapy and combination ranibizumab and laser therapy?

Findings  This post hoc analysis of clinical trial data of biannual fluorescence angiography images of 240 patients and found that capillary dropout and foveal avascular zone regularity did not worsen significantly in eyes treated with ranibizumab injections compared to those treated with laser or combination therapy.

Meaning  Repeated ranibizumab injections were not associated with impaired macular perfusion.


Importance  Anti–vascular endothelial growth factor treatment is the first-line therapy in the treatment of center-involving diabetic macular edema. Data on capillary perfusion changes under repeated treatment in a possibly compromised vascular network are limited.

Objective  To evaluate the association of repeated ranibizumab injections on macular perfusion in patients with diabetic macular edema.

Design, Setting, and Participants  This study analyzed prospectively collected data from the 12-month RESTORE core study and the 24-month open label RESTORE extension study, which assessed the efficacy and safety of ranibizumab in patients with visual impairment due to diabetic macular edema. Of 345 patients with center-involving diabetic macular edema who had enrolled in the 12-month RESTORE core study, 240 entered the 24-month RESTORE extension study. Of these, 83 (34.6%) received ranibizumab, 83 (34.6%) received ranibizumab and laser combination therapy, and 74 (30.8%) received laser monotherapy in the first year of the study; 208 completed the 24-month extension study. Fluorescence angiography images were taken from each participant twice each year graded by Vienna Reading Center on severity of capillary loss in the parafoveal area, regularity of the foveal avascular zone outline, and measurement of the size of the foveal avascular zone, following a standardized protocol. Data analysis took place from July 2014 through December 2017.

Main Outcomes and Measures  Change in 3 fluorescence angiography perfusion parameters over the course of treatment.

Results  Mean (SD) patient age was 62.6 (8.8) years; 124 of 208 (59.2%) were male and 197 of 208 (94.6%) were white. The number of patients with definite altered foveal avascular zone regularity at baseline was 103 of 240 patients (42.9%); another 118 patients (49.2%) had questionably altered regularity at baseline. Definitive capillary loss was found in 65 of 240 patients (27.1%) at baseline. Mean (SD) foveal avascular zone size at baseline was 0.261 (0.232) mm2 in ranibizumab monotherapy, 0.231 (0.219) mm2 in ranibizumab and macular laser combination therapy, and 0.201 (0.13) mm2 in laser monotherapy. No treatment arm experienced significant increase in foveal avascular zone size at any time in the study period. At month 36, ranibizumab monotherapy resulted in a mean increase of 0.073 mm2 (95% CI, 0.005-0.142 mm2) and combination therapy resulted in a mean increase of 0.117 mm2 (95% CI, 0.045-0.188 mm2), but no changes were statistically significant. No changes occurred in foveal avascular zone regularity in any treatment group, and no differences were found in capillary loss around the fovea in the 3 treatment groups; neither element could be correlated with visual acuity or central retinal thickness.

Conclusions and Relevance  Repeated ranibizumab treatment was not associated with impaired macular perfusion in our study cohort. Because our data do not suggest a harmful effect of anti–vascular endothelial growth factor therapy on capillary integrity, patients with severe microangiopathy and advanced capillary dropout should not be denied these treatments.