Intraocular pressure should be monitored in eyes receiving ranibizumab

Retrospective analysis of intraocular pressure (IOP) data from two phase III trials indicates that IOP should be monitored in patients with age-related macular degeneration (AMD) who receive ranibizumab, a recombinant humanized monoclonal antigen binding fragment that neutralizes all active isoforms of vascular endothelial growth factor (VEGF) A.

The two pivotal studies — the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration (MARINA) and Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR) trials — demonstrated that intravitreal administration of ranibizumab significantly improves and maintains visual acuity in patients with wet AMD.

Although there were no meaningful differences in the mean pre-injection IOP at baseline or at any of the monthly follow-up visits in MARINA or ANCHOR, several publications have since reported long-term sustained elevation of IOP in a small subset of patients who received intravitreal injections of anti-VEGF agents for the treatment of neovascular (wet) AMD.

IOP characterization over time

Sophie J. Bakri, M.D., with the Department of Ophthalmology at Mayo Clinic's campus in Rochester, Minnesota, led a team comprising colleagues from across the United States to analyze data from MARINA and ANCHOR.

The goal was to compare the incidence of pre-injection IOP increases in the ranibizumab versus the sham or photodynamic therapy (PDT) groups and characterize further the pre-injection IOP over time during the 24-month treatment period. Results of the team's post hoc analysis were published in Ophthalmology in 2014.

"There were limitations for using these phase III studies to evaluate IOP events," says Dr. Bakri. "The design of inclusion and exclusion criteria in these studies was not guided by specific needs likely to be present in an IOP-focused or a glaucoma-specific protocol." The limitations resulted from:

  • Multiple techniques for measuring IOP
  • Nonstandardized time of measurement for baseline and subsequent IOPs
  • No stratification at baseline for pre-existing IOP or glaucoma risk factors and medications
  • No central corneal thickness measurements, gonioscopy, visual fields, nerve fiber layer assessments or detailed optic nerve examinations

One eye of each patient, the study eye, was treated in MARINA and ANCHOR. In their retrospective analysis, Dr. Bakri and her team identified pre-injection IOP measurements for 1,125 study eyes and fellow eyes in both studies at baseline and at each monthly visit through month 24.

"We evaluated a range of IOP end points using absolute values, because absolute IOP is an important factor in determining whether to treat elevations of IOP," says Dr. Bakri.

Evaluation end points

  • Maximum pre-injection IOP during the 24-month treatment period
  • Any occurrence of absolute pre-injection IOP of 21 mm Hg or more, 25 mm Hg or more, or 30 mm Hg or more
  • Any occurrence of IOP increase of 6 mm Hg or more, 8 mm Hg or more, or 10 mm Hg or more from baseline
  • Any combination of IOP increase of 6 mm Hg or more or 8 mm Hg or more from baseline with concurrent absolute pre-injection IOP of 21 mm Hg or more or 25 mm Hg or more
  • Glaucoma-related adverse events
  • New glaucoma medications used for 45 days or more
  • Glaucoma filtration or laser surgeries

"An IOP of 30 mm Hg or more or an IOP increase of 10 mm Hg or more from baseline is used frequently as an end point when assessing IOP elevations after intravitreal injections," says Dr. Bakri. "Because an absolute IOP end point may miss clinically relevant increases, however, this study also evaluated a combined IOP end point incorporating change from baseline and concurrent IOP."

When evaluating the combined end point rather than an absolute IOP end point, researchers found that more ranibizumab-treated eyes had at least one IOP increase from baseline of 6 mm Hg or more or 8 mm Hg or more, with concurrent highest IOPs of 21 mm Hg or more (26.1 percent and 16.8 percent, respectively) and 25 mm Hg or more (9.6 percent and 7.5 percent, respectively) compared with sham or PDT treatment (13.6 percent and 9.0 percent, and 3.7 percent and 2.4 percent, respectively).

Other findings showed that relatively few study eyes demonstrated a sustained pre-injection IOP of 21 mm Hg or greater over more than two consecutive visits in the course of 24 months. For all treatment groups, the proportion of eyes with elevated IOP from baseline decreased as the number of consecutive visits increased.

This study indicates that for some patients, intravitreal injections may have an effect on IOP, possibly because of the injection volume, the injected drug or both. Sustained elevation can occur after either a single or repeated intravitreal injections, may require IOP-lowering therapy, and may develop in patients with no history of glaucoma.

"It is important to be aware that, although uncommon, sustained IOP increase after intravitreal ranibizumab injections is possible. The treating ophthalmologist should check pre-injection IOP at each visit and initiate further evaluation as appropriate," says Dr. Bakri.

For more information

Bakri SJ, et al. Intraocular pressure in eyes receiving monthly ranibizumab in 2 pivotal age-related macular degeneration clinical trials. Ophthalmology. 2014;121:1102.