Because of their ability to reduce edema and new blood vessel growth in the back of the eye, anti-vascular endothelial growth factor (anti-VEGF) medications are used to treat a number of retina-related conditions. These include wet (or neovascular) age-related macular degeneration (AMD), diabetic macular edema (DME), retinal vein occlusion (RVO), and choroidal neovascularization (CNV). To best assist the ophthalmologist and provide education to the patient, the ophthalmic professional should gain a basic understanding of anti-VEGF medications.

A new treatment paradigm

Treatment of retinal conditions with anti-VEGF medications is relatively new. The first on the scene was bevacizumab (Avastin, Genentech); however, this was initially used in the treatment of cancer in 1997 and approved for the treatment of colon cancer by 2004. Soon after, pegaptanib (Macugen) was approved as the first intravitreally administered anti-angiogenic therapy; Avastin was administered intravitreally as an off-label treatment for VEGF-driven ocular disorders.^1,2

Genentech also created ranibizumab (Lucentis) in hopes of better retinal penetration to reach the choroid and a pan-VEGF A blockade compared to pegaptanib’s effect of only blocking the 165 isoform of VEGF A. The fourth anti-VEGF, aflibercept (Eylea, Regeneron), has a 100-fold increase in binding affinity to receptor sites when compared to ranibizumab and bevacizumab. The application of Eylea has been shown to allow for dosing every 2 months and still be as effective as Lucentis, which is dosed monthly.³

These initial trials were pivotal in establishing the utility of anti-VEGF drugs in the treatment of ocular neovascularization. What we may notice in clinic to be more prevalent, and accordingly cementing the role of intravitreal anti-VEGF medications, are their use in the treatment of DME. While Avastin is still used off-label in the treatment of DME, both Lucentis 0.3 mg and Eylea 2.0 mg are FDA approved to treat DME and diabetic retinopathy. Multiple clinical trials have shown that anti-VEGF use is superior to that of focal laser to treat center-involved DME and may in some cases be superior to another pharmaceutical treatment option, intravitreal steroid injections.^4-6

With the knowledge of these drugs established, it is important to apply their clinical and biochemical effectiveness in the quality-adjusted life-year (QALY) metric, which compares length of life and quality of life in a single measure.

Treat-and-extend benefits for patients

As it currently stands, the ophthalmology community has an expectation of patients with ocular neovascularization to return monthly for a clinical encounter encompassing a full exam, appropriate imaging, and more than likely an intravitreal injection with an anti-VEGF medication. This burden on patients cannot be overlooked given the age of the patients we see in clinic.

An alternative methodology, treat and extend, has been proven efficacious in numerous studies and adopted by many retinal specialists nationwide. A study published in Ophthalmology used a multi-center, randomized study design to subject 441 patients with a treat-and-extend protocol in which they were given injection of either Avastin or Lucentis for 4 weeks until inactive disease was achieved. Following this, the treatment interval was extended by 2 weeks each time, up to a maximum of 12 weeks. At 2 years, both medications had an equivalent and positive outcome on visual acuity and reduction of central retinal thickness.⁷

Freund et al provided a detailed analysis and algorithm on how to extend time between treating patients and when these patients should be brought in for more frequent anti-VEGF injections.^8,9 Essentially, patients receive injections monthly until retinal fluid is absent on OCT for at least 2 consecutive injections, no new hemorrhage or PEDs are present, and there has been no further improvement of vision, at which point the treatment interval is increased by 2 weeks. If the aforementioned criteria are not met and/or new pathology emerges or vision worsens, the interval is reversed. The interval may be extended up to 12 weeks, and, in some cases, treatment may be halted. In this manner, the treatment burden may be lightened without sacrificing maximal treatment benefit.

Practice, staff, and financial considerations

The above data shows that this approach benefits patients, both medically and in terms of lifestyle, and lightens the load for retina specialists, clinics, and their staff.

Financially a huge benefit may be apparent here in terms of reimbursement. Patients with single insurance Medicare incur a 20% copay for these medications. Avastin, which is about $50-60, poses little issue for most patients, but other intravitreal injections can cost up to $1,950. The 20% copay for these injections would weigh heavily on the majority of patients, especially if required every month for an indefinite time; extending patients may give them time to save and practices time to go through foundations of drug companies to assist their patients. Additionally, as most insurances reimburse the drug within 30-90 days, a practice takes less risk with each patient and secures its revenue per-injection with tangible dollars as opposed to awaiting debt payments that may fail to come through on time. This ensures the following months medications can be ordered on-time without incurring much risk.¹⁰

Another consideration is that anti-VEGF injections are not simply an in-and-out procedure as many physicians may think. Dr. Christina Weng from the Cullen Eye Institute timed each step that goes into the procedure and found, on average, this process took 32 minutes and 58 seconds to perform. This time in concert with the overhead costs, materials, and labor (which is not limited to the act of performing the injection, but also prepping, counseling, and ordering the drug) can sometimes lead to a net-negative payout.¹¹

Further analysis of cost-effective options does come up with differing conclusions in terms of which anti-VEGF therapy is the ideal choice for the patient. Stein et al proposed that given the QALYs of Avastin vs. Lucentis, both are equal in nature. Despite Avastin being more accessible to patients given its cost and, by virtue of that, its availability, Lucentis seems to confer greater therapeutic effects. The utility of QALYs in this article goes one step further to also suggest that, given the side effect profile, intravitreal steroids, such as triamcinolone, should be surpassed by Lucentis in regards to payout by insurance companies.¹²

Conclusion

Individualized anti-VEGF treatment can deliver tailored care to patients while simultaneously relieving clinics of the burden of the back-and-forth with insurance companies and patients for payment. Additionally, this can allow physicians to run clinics that allow for more face-to-face discussion with patients as opposed to running from room to room administering injections.

Many new products are on the horizon as well, potentially offering more spaced out dosing regimens, fewer doses, and similar efficacy, thus increasing the potential for this treatment to become less burdensome and someday drive down the overall costs of medications. OP

REFERENCES:

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4. Soheilian M, Garfami KH, Ramezani A, Yaseri M, Peyman GA. Two-year results of a randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus laser in diabetic macular edema. Retina. 2012;32(2):314-321.
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9. American Academy of Ophthalmology. EyeNet Magazine. Treat-and-Extend Strategy: Is There a Consensus? www.aao.org/eyenet/article/treat-extend-strategy-is-there-consensus . Accessed August 11, 2020.
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11. Medscape. Eye Injections Cost More Than Payers Think. https://www.medscape.com/viewarticle/916132 . Accessed August 11, 2020.
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