February 13, 2017
4 min read

From the outside looking in at anti-VEGF therapy

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Richard L. Lindstrom

As an anterior segment surgeon, I am a little out of my comfort zone commenting on the details of the many studies evaluating the indications and outcomes after the use of anti-VEGF therapy. I do not perform intravitreal injections of anti-VEGF, nor do any of the 26 doctors at Minnesota Eye Consultants. We do, however, have many patients in our practice who are being treated by retina specialist colleagues.

My first impression is that intravitreal anti-VEGF therapy for wet age-related macular degeneration, diabetic retinopathy and macular edema from a host of causes has been an extraordinary advance — as important to ophthalmology as the development of phacoemulsification and IOLs.

My second impression is that anti-VEGF therapy is very expensive for both the individual patient and society as a whole if the so-called branded FDA-approved drugs are utilized. The Medicare allowable for Avastin (bevacizumab, Genentech) is $69, for Lucentis (ranibizumab, Genentech) is $1,189 and for Eylea (aflibercept, Regeneron) is $1,961. The expenditure on these drugs by CMS is approaching 25% of the entire Part B Medicare drug expenditure. As indications expand, the population ages, and the number of Americans with diabetes and wet AMD grows, one has to be concerned that the cost of anti-VEGF therapy will break the bank. We have been challenged by our federal government to pursue the “triple aim” — generate good outcomes, achieve high patient satisfaction and reduce costs. While I strongly believe that a good return on investment for the pharmaceutical industry is required to catalyze investment and the innovation cycle, the cost of anti-VEGF drugs is stressing many countries’ health care budgets and may soon do the same in the U.S. I do not have the answer, but in the field of cataract surgery, innovation over time significantly reduced the cost per case as surgical volumes expanded. The same needs to occur for anti-VEGF therapy.

My third impression is that, for many indications, the outcomes achieved with the three drugs available are equivalent. This suggests to me that the lower-cost alternatives are reasonable for many patients. However, for some indications, such as diabetic macular edema presenting with a visual acuity of 20/50 or worse, the selection of Eylea seems indicated by the superior outcomes achieved in the Protocol T studies: 19 letters of improvement for Eylea vs. 14 for Lucentis and 12 for Avastin at 1 year. Eylea also generated a greater reduction in macular thickness, with 169 µm for Eylea, 147 µm for Lucentis and 101 µm for Avastin.

Fourth, it is important for the comprehensive ophthalmologist to be familiar with the side effects and adverse events associated with these injections. In most studies the most common complications were vitreous hemorrhage in about 3% of cases and elevated IOP in about 11%. Systemic side effects, including cardiovascular events, were rare and similar with all three drugs. Endophthalmitis is very rare, less than one per 2,000.

Fifth, of interest to me in the Protocol T study was that when using a treat-and-extend approach, just more than nine injections were given by 1 year, slightly less than the earlier recommended one per month. While the original protocols in wet AMD required an anti-VEGF injection every month and in the recent Protocol T study nine injections were given in the first year, real-world studies suggest that many if not most patients outside the clinical trials receive fewer than six injections per year. The burden on the patient, their family and even the ophthalmologist providers is just too great to sustain nine to 12 injections a year for many years on end. Thus, real-world results for visual improvement do not match the outcomes obtained in the clinical trials. This challenge begs for innovation in our delivery models, with telemedicine for diagnosis and perhaps specially trained nurses in rural communities for the injections. In addition, the three-line improvements obtained at 1 year fade by 3 to 4 years. Some of this is likely related to an inability to sustain nine to 12 injections a year. Some is also related to wet AMD progressing to geographic atrophy of the macula after years of anti-VEGF therapy. So, while the outcomes of anti-VEGF therapy are initially a great success for many patients, most will still progressively lose vision over subsequent years. This loss is disappointing to patients, and they need counseling, support and low vision aid consultation as their vision deteriorates.


Sixth, the unexpected and for many investors shocking failure of the anti-PDGF/anti-VEGF combination is a major setback for ophthalmology. I hope the great losses incurred by venture capital investors and their partner communities do not negatively impact investment into new treatments as there are still many unmet needs in our field.

My final impression is that the learnings from the DRCR.net retina specialist/industry consortium have been nothing short of amazing. We need to create a similar collaboration in anterior segment surgery as there are many important questions to answer in cataract, glaucoma and corneal surgery and disease. The American Society of Cataract and Refractive Surgery has created an ASCRS Research Council that will initially study the impact of topical antibiotics vs. intracameral antibiotics in the prevention of post-cataract surgery endophthalmitis. This is a good start, as is the consortium of corneal surgeons that has answered several important questions in corneal preservation and keratoplasty through the Cornea Donor Study Group. Our group at Minnesota Eye Consultants participated in the Cornea Donor Study Group Research Protocols and intends to participate in the ASCRS Research Council. I encourage my private practice colleagues to support and participate in these clinical trials. More collaborative research performed together by academic and private practice ophthalmologists and funded by industry and government together is needed to fuel the innovation cycle and help preserve, restore and enhance the vison of our patients.

Disclosure: Lindstrom reports no relevant financial disclosures.