Anti-vascular endothelial growth factor agents have become the standard of care for the treatment of neovascular age-related macular degeneration, retinal vein occlusions and diabetic macular edema. Pivotal clinical trials have shown dramatic improvements in vision associated with anti-VEGF agents and, correspondingly, the clinical utilization of anti-VEGF agents has trended upward.1 However, despite the abundance of evidence that more frequent injections lead to the best visual outcomes, clinicians are, on average, treating patients substantially less frequently. This article will review “real-world” usage of anti-VEGF medications for three Food and Drug Administration-approved intravitreal indications: AMD; RVO; and DME.


Anti-VEGF therapy was first approved for intraocular use in neovascular age-related macular edema. Ranibizumab was initially approved in the United States for neovascular AMD in 2006, the same year as the pivotal ANCHOR2 and MARINA3 trials were published. These large prospective trials reported that monthly ranibizumab injections led to +11.3 and +7.2 Early Treatment of Diabetic Retinopathy letter gains overall at 12 months, respectively. Less-frequent injection dosing in PIER,4 which dosed patients monthly for three months and then quarterly up to month 12, revealed an initial +4.3- letter improvement at month three then a total -0.2 decrease by month 12 after less-frequent dosing was initiated. Similarly, in EXCITE,5 less-frequent dosing led to fewer letter gains compared to the pivotal Phase III trials. Patients in EXCITE were treated monthly for the first three months then switched to quarterly dosing or maintained on monthly dosing. Those remaining on monthly ranibizumab dosing for the 12 months achieved +8.3 letters versus the two quarterly groups, which gained +4.9 and +3.8 letters.

The two-year CATT data appear to support the findings of less-frequent injections resulting in fewer letters gained. In CATT, patients reassigned from monthly to PRN administration after the first year had a reduction in vision (-1.8 letters in the ranibizumab group and -3.6 letters in the bevacizmuab group; p=0.03) compared with patients that continued on the monthly regimen.6,7 Monthly regimens in the ranibizumab and bevacizumab groups led to gains of +8.8 letters and +7.8 letters at 24 months, respectively, versus +6.7 and +5.0 letters in the p.r.n. groups. Compared to a maximum of 26 injections in the fixed monthly dosing, p.r.n. groups averaged 12.6 treatments and 14.1 treatments over the two years. The IVAN8 and HARBOR9 prospective trials also revealed small visual acuity differences between the monthly and p.r.n. groups (<three letters), which were not statistically significant.

Despite the data in the literature of the apparent benefit of frequent anti-VEGF dosing, large retrospective analyses of claims from that time period show an apparent under-utilization of anti-VEGF agents.1,10,11 Nancy Holekamp, MD, and colleagues analyzed United States claims data from 2006 to 2010 for ranibizumab and bevacizumab use for neovascular AMD.1 In the 2006 and 2007 cohorts (n=8,767), mean annual numbers of bevacizumab or ranibizumab injections were 4.7 and 5.0 respectively. In the 2008 to 2010 cohorts (n=10,259), mean annual numbers of injections were 4.6, 5.1 and 5.5 for bevacizumab; and 6.1, 6.6 and 6.9 for ranibizumab. In an international real-life utilization study, the mean injection numbers in Canada, France, Germany, Ireland, Italy, the Netherlands, the UK and Venezuela were also lower than in the large prospective clinical trials.10 Data from 2009 to 2011 were analyzed in these eight countries for 2,227 patients with neovascular AMD. Overall, patients received a mean of 5.0 injections in the first year of treatment and 2.2 injections in the second year. This corresponded to a mean change in visual acuity of +2.4 and +0.6 letters in years one and two, respectively. Of note, this study suggests that in countries where patients received more frequent injections, the visual acuity gain was higher. This ranged from the lowest-ranking country, Italy, with a net loss of -2.1 letters at year two (zero gain at year one) with a two-year mean of 5.2 injections to the highest-ranking country, the UK, with a net gain of +4.1 letters at year two (+6.0 letters at year one) with a two-year mean of 9.0 injections.

Additionally, clinicians are seeing neovascular AMD patients and ordering diagnostics tests much less frequently than in the clinical trials.11 In an analysis of more recent U.S. claims data, while the mean number of injections increased from 2008 to 2010, less than 23 percent and less than 40 percent of patients had at least 10 annual ophthalmologist visits in the bevacizumab and ranibizumab-treated patients, respectively. Less than 14 percent and less than 21 percent of patients had at least 10 optical coherence tomography scans in these respective groups for the 2010 cohort. These real-world data reveal that patients are being seen less frequently, are receiving fewer injections, and are gaining fewer letters than patients in the prospective clinical trials.


Ranibizumab was FDA-approved for use in central retinal vein occlusion and branch retinal vein occlusion in 2010. The use of monthly anti-VEGF when compared to the standard-of-care (observation for CRVO and focal laser as needed for BRVO) in RVO was associated with significant improvement in visual acuity in both the BRAVO12 and CRUISE13 studies.
Despite mounting evidence that monthly monitoring and more frequent injections lead to better and more sustained visual outcomes, practitioners are underutilizing anti-VEGF therapy in patients with neovascular AMD, RVO and DME. 
In both studies, patients received either sham injections or monthly ranibizumab dosing (0.3 mg or 0.5 mg) for the first six months followed by p.r.n. dosing. Vision improved by +16.4 and +18.3 letters in the BRAVO treatment groups compared to +12.1 in the sham group, with an average of 8.4 injections in the 12 months. In the CRUISE study, vision improved by +13.9 letters in both dosing arms of the treatment groups versus +7.3 letters in the sham group with an average of 8.8 injections administered. Although fewer pivotal trials were conducted in RVO than in neovascular AMD, data from the extension phases of BRAVO, CRUISE and HORIZON14 suggests a similar association between dosing frequency and visual improvement.

In a claims analysis from 2008 to 2011, a total of 885 BRVO and 611 CRVO patients were included. In the 2008, 2009 and 2010 cohorts, mean annual injections were 2.5, 3.1 and 3.3 for BRVO and 3.1, 3.1 and 3.5 for CRVO respectively.15 Visual acuity data for this claims analysis is not available; however, patients clearly received less frequent dosing than suggested by the results of BRAVO and CRUISE. In addition, patients in these cohorts saw their ophthalmologists infrequently, averaging between 5.1 to 5.6 visits in the BRVO groups and 5.8 to 6.5 visits for the CRVO patients.


Anti-VEGF therapy was approved for the treatment of diabetic macular edema in 2012 and therefore, we have the least understanding of its real-world clinical utilization. Nevertheless, the same pattern of apparent underutilization can be seen when clinical use data is compared to prospective pivotal trial data. As with AMD and RVO, large studies for anti-VEGF therapy in DME also suggest that better visual acuity comes with more frequent injections. RESOLVE,16 RISE/RIDE17 and protocol T18 used more frequent injection regimens and achieved greater mean numbers of letters gained over 12 months compared to studies like RESTORE19 or Protocol I20 with less-frequent p.r.n. dosing regimens. In RESOLVE, there was an average of 10.2 injections with a +10.3-letter gain (-1.4 letters for sham group). RISE/RIDE had monthly injections with +10.9 ±12.5 letter gain versus +2.3 ±2.6 for the sham groups. protocol T averaged between nine and 10 injections across the aflibercept, bevacizumab and ranibizumab groups with overall letter gains ranging from +9.7 to +13.3.

By contrast, RESTORE patients averaged 6.8 to 7.3 injections with a +6.4 to +6.8 letter gain versus +0.9 for the laser alone group. While in protocol I, patients in the injection or injection plus prompt laser averaged nine and eight injections respectively, with a +9.0 letter gain in both groups.

In analyses of real-world data, the mean number of injections for DME appears to be considerably less than the prospective trials. A claims analysis revealed between 2.2 and 3.6 injections per year for newly diagnosed DME patients.15 These numbers are in stark contrast to the mean numbers in the large clinical trials noted above. Furthermore, only 31.2 percent of patients with newly diagnosed DME received three or more injections in the first four months of treatment.15 Again, the real world use of anti-VEGF medications is substantially less than in clinical trials.

Reasons for Underutilization

There are many factors that may contribute to the lower numbers of injections and office visits seen in clinical practice when compared to prospective studies. Patients in a clinical practice may be inherently different from those enrolled in large clinical trials. The stage of the disease in patients treated in the real world may not be comparable to that in the trials. Practitioners may also be slow to adopt increased dosing regimens, and the claims data analyzed for the clinical utilization data may subsequently capture this lag.

In addition, treatment burden for patients and their caregivers may also play a large role. Many of these patients, especially those with vascular diseases like diabetes or hypertension, have numerous doctors’ visits each year and therefore are not willing or able to see their ophthalmologist on a monthly or close to monthly basis.21 Additionally, there are some studies that have shown that extended treatment protocols, such as treat-and-extend for neovascular AMD, may provide comparable results to monthly retinal evaluations and anti-VEGF injections.

Despite mounting evidence that monthly monitoring and more frequent injections lead to better and more sustained visual outcomes, practitioners are underutilizing anti-VEGF therapy in patients with neovascular AMD, RVO and DME. This underscores the need for further innovation to reduce the burden on patients, caregivers and the health-care system associated with treatment of these disorders. In the future, perhaps sustained-delivery devices or gene therapy may provide a means for reducing office visits and intravitreal injections without sacrificing visual outcomes.  REVIEW

Dr. Berenberg is a second-year surgical vitreoretinal fellow, and Dr. Kiss is an associate professor of ophthalmology, both at the Weill Cornell Medical College. Contact Dr. Kiss at, or (646) 962-2217.

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