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Intravitreal injections of agents intended to inhibit vascular endothelial growth factor (VEGF) activity are commonplace in many retinal practices. They are used for treating many ocular conditions including wet macular degeneration and in retinal vascular diseases including retinal vein occlusions and diabetic retinopathy. Extrapolating from data on the aging US population suggests a further explosion in the prevalence of many of these age-related eye diseases and other chronic conditions with ocular involvement, meaning the demand for anti-VEGF injections will likely continue to rise. The sheer volume in the number of patients that will need intra-vitreal injections has the potential to overwhelm already busy retinal practices.
Despite the already high volume of usage and suggestion that the popularity of anti-VEGF therapy will continue to rise, there are no established clinical care guidelines between optometry and ophthalmology that help define comanagement principles for these patients. In this vacuum, it is incumbent on any optometrist who detects pathology that requires referral for anti-VEGF injection(s) to know and understand what is involved in delivering these injections so that he or she can better educate patients at the appropriate time. Although anti-VEGF therapy can be applied to a number of diseases of both the anterior and posterior segment, this article focuses primarily on anti-VEGF therapy as it is applied to common retinal pathologies—including age-related macular degeneration and retinal vascular disease—and to macular edema that results from these same conditions, including diabetic retinopathy.
THE INITIAL WORK-UP
Determining the health of the retina and the macula in particular by way of a dilated fundus examination is essential for any patient with suspected retinal pathology. In fact, this should be the standard of care for all patients at some point. It is also important to look at the entire retina, including the periphery, given that many retinal diseases are not confined to central involvement.
The use of spectral-domain optical coherence tomography (SD-OCT) has emerged as the primary tool used by retina specialists for assessing and following patients, as it adds to the sensitivity and specificity for detecting subtle architectural changes that are suggestive of pathology. As an optometrist, it may be impossible to be taken seriously as a partner in the management of patients with retinal pathology without an SD-OCT in his or her office. Part of building a working relationship with a retina specialist, beyond accurately diagnosing cases that need further follow-up, is establishing trust. This can only be done if you have the necessary tools at your disposal to effectively diagnose and manage even the subtlest cases that cannot be seen or diagnosed without this technology. Indeed, for optometrists hoping to comanage patients with retinal diseases, SD-OCT is an absolutely essential tool.
Other imaging modalities—namely fundus photography and fundus autofluorescence—are additive in the entire clinical impression and do not supplant the physical examination in the setting of suspected retinal disease. As important as OCT has become in the diagnosis and management of retinal disease, all these technologies should always be used in conjunction with the entirety of the examination in making clinical decisions on management and treatment.
Educating patients before a referral to a retina specialist is important so they know what to expect in terms of diagnostic testing as well as what other procedures may be performed, including intravitreal injections. Patients should have an understanding of how their particular condition has the potential to affect their vision.
In my experience, telling patients they have a condition that may require surgery or an injection into their eye can induce a high degree of fear or anxiety, which can be detrimental to having a meaningful conversation with the patient. Being able to physically show your patients an image of the back of their eye and being able to point to and illustrate how their condition is affecting the health of their retina may help them to understand their condition and hopefully overcome that barrier. Giving patients time to absorb the information without overwhelming them is another aspect of effective education.
It is only fair to let patients know that the retina specialist will likely repeat many of the same diagnostic tests performed during their initial workup, as well as possibly performing a fluorescein angiogram.
OUTCOMES: SAFETY AND EFFICACY
Intravitreal anti-VEGF injections are commonly performed in the eye care setting. Although typically associated with treatment of age-related macular degeneration, anti-VEGF therapy has indications for macular edema secondary to diabetic retinopathy and retinal vein occlusions. It has also been studied for the treatment of several neovascular disorders affecting both the anterior and posterior segment, such as the previously named conditions as well as neovascular uveitis with or without associated glaucoma and iris neovascularization. There have been investigations into using anti-VEGF therapy in the setting of retinopathy of prematurity, although no definitive data yet exist for that usage.
The popularity of anti-VEGF agents for the treatment of ocular conditions follows from the role of VEGF in angiogenesis. Specifically, ischemia, which is commonly seen in a number of different retinal vascular diseases, results in increased production of VEGF. This in turn stimulates the growth of new blood vessels in response to the ischemia. Increased VEGF production also results in increased capillary permeability, which may lead to the development of macular edema. In age-related macular degeneration, inflammation also plays a critical role in the production of VEGF. Based on this scientific rationale, it makes sense that if VEGF could be blocked, then specialists might be able to (1) prevent the development of neovascularization and (2) decrease macular edema by reducing capillary permeability. This scientific rationale led to the development of anti-VEGF drugs, including bevacizumab (Avastin, Genentech), which is approved by the US Food and Drug Administration (FDA) for use in oncology to treat metastatic colorectal cancer (because angiogenesis plays a role in tumor growth).
The first anti-VEGF agent approved by the FDA for ophthalmic use was pegaptanib sodium (Macugen, Eyetech) in the early 1990s. It was approved for the treatment of choroidal neovascularization (CNV) associated with wet AMD and it was the first treatment to show a positive affect for occult CNV. As good as pegaptanib sodium seemed to be, however, it was nowhere near as effective as ranibizumab (Lucentis, Genentech), which was developed shortly after. In clinical trials, ranibizumab demonstrated that not only did the therapy abate visual acuity loss, but some patients actually regained a significant degree of functional vision.1,2
Interestingly, while ranibizumab was going through clinical trials, clinicians began using off-label bevacizumab as it was believed that bevacizumab and ranibizumab were functionally the same molecule. Ranibizumab is a monoclonal antibody fragment derived from bevacizumab. Bevacizumab had already received FDA approval for treating metastatic colorectal cancer, and when compounded for ocular use, it is only a fraction of the cost of ranibizumb. Several clinical trials, including the Comparison of Age-Related Macular Degeneration Treatment Trials (CATT)3 and Alternative Treatments to Inhibit VEGF in Age-Related Choroidal Neovascularization (IVAN),4 have shown that both drugs have essentially equal efficacy. As a result, bevacizumab has emerged as a popular treatment choice.
In late 2011, the FDA approved aflibercept (Eylea, for- merly VEGF Trap-Eye, Regeneron Pharmaceuticals/Bayer HealthCare) for the treatment of AMD based on phase 3 studies showing that it was noninferior to ranibizumab (the current standard of care).5,6 Patients in those studies demonstrated an anatomical response (eg, a reduction in central retinal thickness) and mean gains in visual acuity. All of the study groups showed similar rates of systemic vascular events.
There is clear evidence for the safety and efficacy of anti-VEGF agents in all of the major studies.1,2,5,6 Many questions still remain about these agents, however, including the most appropriate dosing frequency and whether the off-label use of bevacizumab is safe. There is a scientific hypothesis that bevacizumab, because it has a longer half-life but has less affinity for VEGF compared with ranibizumab, might have increased systemic availability, and thus it may induce more systemic adverse events.
In an attempt to resolve some of these concerns, the National Eye Institute of the National Institutes of Health sponsored CATT comparing bevacizumab and ranibizumab in different dosing schemes (ie, as-needed therapy vs scheduled monthly dosing). In reporting the 2-year outcomes from the study, researchers noted that rates of death and arteriothrombotic events were similar for both drugs, although a greater proportion of patients in the bevacizumab group experienced one or more serious adverse events, with higher rates reported among patients being treated in the as-needed protocol versus monthly dosing. However, when all known VEGF-related adverse events were excluded from the analysis, rates were still higher among bevacizumab-treated patients, and thus, it was inconclusive whether the events were related to the study drug or chance.3 In short, the importance and clinical significance of this finding are still being investigated.
There is some associated risk with anti-VEGF agents, and of principal concern is the potential for endophthalmitis. A major review of 14,866 injections in 4,382 eyes published in 2004 found a prevalence rate of endophthalmitis occurrence of about 0.3%.7 The procedure for delivering anti-VEGF therapy has been refined since that time, so it could be that the rate is even lower today. Yet, because the complication has vision-threatening consequences, it is still something to be aware of.
Spikes in intraocular pressure have been noted after intra-vitreal injections of anti-VEGF agents8; however, they are largely transient and self-limiting. Because of this, however, patients with glaucoma or those at risk for pressure elevations require special monitoring.
The most popular dosing regimen with anti-VEGF therapy for the treatment of CNV in AMD is a minimum of three loading doses during 3 consecutive months, followed by a period of as-needed therapy, with retreatment largely based on changes on repeat OCT imaging. What this means is that a referred patient is likely to return to the specialist for follow-up care and monitoring for the first 6 to 8 months of therapy. This may be a conservative estimate, and the amount and length of follow-up will vary based on patients’ responses to therapy.
For optometrists, there is likely little opportunity for postinjection comanagement of these patients during this interval, with a few exceptions. The first setting is for those optometrists who work in integrated care practices where there is an established protocol for postinjection care. The second scenario would entail practitioners in rural settings. Patients who have long commutes to see a retina specialist may prefer to return to their optometrist for follow-up screening because it is convenient and/or based on the established relationship that the optometrist has developed with the treating physician. Having the necessary diagnostic equipment as well as knowledge and understanding of the retreatment criteria and the potential safety signals is especially important for optometrists who function as a care extender. Other than these special circumstances, it is unlikely that referred patients will return to the practice until their disease is stable. Therefore, in the interest of patient retention, optometrists may want to think about trying to develop a trusting working relationship with the retinal specialist with the ultimate hope of being able to establish an agreement or a protocol for referral that takes into account the needs of the patient while allowing the optometrist and surgeon to function efficiently in their respective practices. Perhaps in this digital era, some treating physicians may even prefer having patients’ retinal images e-mailed to them for a quick evaluation on determining if the patient needs to be seen by the retinal specialist.
Intravitreal anti-VEGF injections are commonplace in the care of patients with several retinal pathologies because of the role VEGF plays in angiogenesis and macular edema. The aging population suggests an even greater use of these agents in the near future, so it is incumbent on optometrists to have the tools to effectively diagnose and follow these patients and to establish trust and relationships with specialists for referral purposes. Although there are no formal guidelines surrounding the comanagement of patients in need of anti-VEGF therapy, the sheer volume of patients is likely to become too overwhelming for retina specialists to perform all of the imaging and after care themselves.
Mark T. Dunbar, OD, is the director of optometric services and the optometry residency supervisor at Bascom Palmer Eye Institute, University of Miami. He has no financial interest in any of the products or companies mentioned herein. Dr. Dunbar may be reached at (305) 482-4042; email@example.com.
1. Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431.
2. Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432-1444.
3. Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and bevacizumab for treatment of neovascular agerelated macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388-1398.
4. Chakravarthy U, Harding SP, Rogers CA, et al; IVAN Study Investigators. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology. 2012;119(7):1399-1411.
5. Heier JS. VEGF Trap-Eye Phase III Trial Results. VIEW 1 results. Paper presented at: Angiogenesis, Exudation, and Degeneration 2011; February 12, 2011; Miami, FL.
6. Schmidt-Erfurth U. VEGF Trap-Eye Phase III Trial Results. VIEW 2 results. Paper presented at: Angiogenesis, Exudation, and Degeneration 2011; February 12, 2011; Miami, FL.
7. Jager RD, Aiello LP, Samir P, Cunningham ET. Risks of intravitreous injection: a comprehensive review. Retina. 2004;24(5):676-698.
8. Kim JE, Mantravadi AV, Hur EY, Covert DJ. Immediate intraocular pressure changes following intravitreal injections with anti-VEGF agents. Am J Ophthalmol. 2008;146:930-934.