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From bench to population: The real-world scenario beyond clinical trials
The wide use of anti-VEGF agents has led to an unprecedented change in the way neovascular age-related macular degeneration is being treated. The prognosis of patients affected with neovascular AMD is no longer poor. Landmark trials have proven that 0.5 mg ranibizumab dosed monthly provides optimum results. Most patients are able to maintain their vision without further loss, and about one-third experience improvement in their vision. A number of randomized clinical trials have further underlined the overwhelming benefits of treating with anti-VEGF agents. However, the real-world scenario does not reflect the success stories seen in the clinical trials.
Real-world setbacks
There are a number of setbacks when you try to apply the results of the clinical trials in the real world. The clinical trials are of fairly short duration, evaluating results over 6 months, 12 months or 24 months, whereas AMD is a chronic disease; with increasing life expectancy, the disease is seen to progress for decades. In fact, in the SEVEN-UP study, when subjects treated with Lucentis (ranibizumab, Genentech/Novartis) in the MARINA, ANCHOR and HORIZON trials were evaluated 7 to 8 years after the initiation of treatment, it was seen that 68% of the patients still showed evidence of active exudative disease. And 46% of the patients were continuing to receive intravitreal anti-VEGF treatments. It is concerning to note that even after treatment for a long duration, wet AMD patients are still at risk for significant vision loss. Also, it is clear that we are in no way curing the disease with our anti-VEGF injections. We can at best keep it under control and prevent excessive vision damage.
The chronicity of the disease is the main reason for inability to sustain the treatment, especially with the current recommended dosing regimen of monthly injections.
Factors affecting the dosing interval
Outside the clinical trials, the dosing interval is seen to vary widely. A number of observational studies have concluded that more frequent visits and injections were associated with better outcomes with greater visual improvement. However, it was also noted that a majority of patients, nearly 50% to 75%, did not receive injections after the loading phase. The number of visits on average were as few as one to two per year. Optical coherence tomography was seldom used for evaluation. And more often than not, the visual benefit obtained during the loading phase was lost.
Physicians may have been lulled into complacency by the initial good response to therapy. It would be wise to remain alert to the changes, while at the same time, more specific guidelines for re-treatment need to be laid down. The previous re-treatment criteria have nearly been given up now, and for all practical purposes, any changes in OCT or vision are now taken as an indication to treat. Although there are controversial views about repeating a fluorescein angiogram, when in doubt, it is always better to repeat one and look for leakage.
The cost of the treatment and the burden of frequent office visits are other major deterrents. The patient population in developing nations, as well as developed nations, is finding it difficult to sustain the treatment over a long period. It has also placed a significantly high workload on ophthalmologists’ practices. The clinics are overburdened with scheduling monthly visits and injections for a large number of patients.
The way forward
Various flexible dosing regimens, including as needed and treat and extend, are being employed to give a more tailor-made, individualized treatment to the patient. As-needed dosing with monthly monitoring has been shown to be almost as effective as monthly dosing. Treat-and-extend dosing is being evaluated in prospective clinical trials. Increased awareness about the disease and home monitoring can lead to early detection of visual changes. In all the clinical trials, better final visual acuity correlated well with better initial visual acuity. Self-monitoring with regular Amsler grid testing between ophthalmological visits is suggested. Preferential hyperacuity perimetry (PHP) telemonitoring is a more standardized self-monitoring tool. In the AMD Detection of Onset of New Choroidal Neovascularization Study, the sensitivity of Amsler grid testing, PHP and OCT for detection of choroidal neovascularization was 0.40 for OCT, 0.42 for supervised Amsler grid and 0.50 for PHP. While research is exploring newer molecules and sustained-release drug delivery systems, the Euretina guidelines would help ophthalmologists in recommending optimum treatment options to their patients.
References:
Busbee BG, et al. Ophthalmology. 2013;doi:10.1016/j.ophtha.2012.10.014.
Do DV, et al. Ophthalmology. 2012;doi:10.1016/j.ophtha.2011.10.019.
Rofagha S, et al. Ophthalmology. 2013;doi:10.1016/j.ophtha.2013.03.046.
Schmidt-Erfurth U, et al. Br J Ophthalmol. 2014;doi:10.1136/bjophthalmol-2014-305702.
For more information:
Dennis S.C. Lam, MD, FRCOphth, can be reached at State Key Laboratory in Ophthalmology, Sun Yat-Yen University, 54 South Xianlie Road, Guangzhou 510060, People’s Republic of China; +852-3997-3266; email: dennislam.gm@gmail.com.
Disclosure: Ratra and Lam have no relevant financial disclosures.