“Anti-VEGF therapy results are so good in the clinical trials. But my real-world patients just don’t experience the same great outcomes!  How do I manage patients who don’t respond to anti-VEGF?”  I hear these comments frequently as I chat with other retina specialists about the management of diabetic macular edema.  I often hear variations on this refrain from patients who are referred to me for a second opinion on treatment options following “inadequate response” or “failure” after anti-VEGF therapy for diabetic macular edema (DME). In the DRCR Network we brainstorm with our investigators at least twice yearly for ideas for new protocols. Some of the most common suggestions we get are to perform studies that address which patients will or won’t respond successfully to anti-VEGF treatment, or studies that evaluate new treatment options for incomplete responders.

In clinical practice, I find that many DME patients who have been declared anti-VEGF treatment “failures” are simply individuals who haven’t been given enough anti-VEGF.  They have received too few injections or sometimes have had injections at treatment intervals that are too long to adequately judge response.  I often find that these patients do experience improvements in vision or retinal thickening once they are prescribed a more rigorous schedule and given at least 3 to 6 additional anti-VEGF treatments.  My personal experience has been similar to what we saw in the DRCR.net Protocol U study, which recruited patients who had persistent DME with impaired vision despite at least 3 intravitreous anti-VEGF injections over the previous 5 month.  All these patients were considered anti-VEGF incomplete responders by their physicians.  Study participants received 3 more monthly anti-VEGF injections of ranbizumab after enrollment to ensure that they were true nonresponders.  Of the 203 patients enrolled, 38% (78 patients) no longer met criteria for persistent DME due to improvement in retinal thickening or vision after this initial run-in phase.

So how many injections are needed to establish anti-VEGF nonresponse?  I’ve heard a well-known retina specialist say he switches agents if a patient doesn’t show definitive improvement after a single injection.  I think that is doing the patient a disservice.  There are many eyes that completely resolve their DME and achieve 20/20 or better vision that may not show dramatic improvements within the first 3 to 6 months of anti-VEGF therapy.  In DRCR.net Protocol T, 43% to 51% of eyes that had chronic persistent DME after 6 months of anti-VEGF therapy achieved vision of 20/25 or better by 1 year.  Some physicians use 3 months as a benchmark, citing as evidence for this practice an analysis of the Network Protocol I data that shows that eyes with less visual improvement after 3 months of treatment are, as a group, less likely to experience large average gains in vision with continued therapy over time.  However, this reasoning ignores the large degree of variability in visual recovery that is seen in this group.  Furthermore, many of these eyes still end up with excellent vision.  Sometimes they do not gain large amounts of vision because they started therapy with milder degrees of visual impairment.  I avoid switching therapies as early as 3 months because I know the outcomes with continued long-term anti-VEGF therapy are generally good, and there is no therapeutic alternative that has been proven to work better.

Nonetheless, there are patients whose recovery from DME is limited even after 6 or more anti-VEGF injections.  So what is the best management option for these individuals?  Unfortunately there is no clear answer to this important clinical question.  Protocol U showed us that addition of a sustained-release intravitreous dexamethasone implant does not improve visual acuity, although it does reduce retinal thickening over a follow-up period of 6 months.   Other strategies are to add macular focal/grid laser or to switch anti-VEGF agents, although it is not clear that the latter is an effective strategy for all eyes.  Some eyes that experience improvement after receiving an alternative anti-VEGF agent may do so as a result of continued VEGF suppression rather than the change in drug.  Given the potency of our current anti-VEGF agents, increasing the dose of anti-VEGF is not likely to improve response.  Increasing frequency of dosing does seem to improve response in a few patients who may have faster turnover of anti-VEGF in their eyes, but it is not practical over the long term to require more than monthly dosing for most patients.

For now, my strategy for patients with DME is to treat aggressively in the first few months of therapy, keeping as close to 1 month intervals as I can.  I give at least 6, and often closer to 9, injections of anti-VEGF before I evaluate the need to add or switch treatment modalities.  In my experience, most patients experience some level of improvement over this time period, and patients’ willingness to continue with a prolonged course of anti-VEGF is substantially influenced by their perception of whether they are improving.  As long as their vision is trending upward and retinal thickening is stable or improving, most of my patients are willing to stick with monthly injections.  I emphasize that although they are likely to require frequent, near monthly treatment in the first year of therapy, the need for anti-VEGF diminishes over time.  I also hold on injections once the DME and vision have become and remain stable over 2 or more injection visits.

In the end, there are few eyes that truly qualify as “nonresponders” to anti-VEGF for DME, but there are many eyes that require multiple months of therapy before showing substantial improvement.  Overall, results with anti-VEGF therapy are excellent when adequate numbers of injections at reasonable dosing intervals are given.  There is no question that newer, more effective, more durable, and less invasive therapies are still needed to optimize outcomes in eyes with DME.

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