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Anti-VEGF therapy in studies a different world from daily clinical practice

Issue: October 2014

ByPaolo Lanzetta, MD

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A Different World was an American television sitcom that aired for six seasons in the late ’80s and early ’90s. A group of students at university struggle to make it through college. Similarly, retina specialists throughout the world struggle to translate the excellent outcomes of anti-VEGF therapy as applied within registration trials into daily practice.

Most of the randomized studies that led to the approval of the currently available intravitreal drugs and related treatment and monitoring regimens for severe retinal conditions such as wet age-related macular degeneration, macular edema secondary to vein occlusion, diabetic macular edema and myopic choroidal neovascularization have shown unprecedented figures in terms of visual acuity improvements and prevention of visual loss. Practically, this may mean fewer people living with legal blindness, more people retaining their driving licenses, and a decrease in social costs and disabilities.

Having practiced with laser photocoagulation and photodynamic therapy, when the success of a treatment was defined as only limiting visual acuity loss, as soon as anti-VEGFs came into the field, I left frustration behind and jumped in with excitement and resuscitated enthusiasm.

A number of multicenter trials, such as MARINA, ANCHOR, VIEW, HARBOR and CATT for wet AMD; RIDE/RISE, RESTORE, VIVID and VISTA for diabetic macular edema; CRUISE, BRAVO, COPERNICUS, GALILEO and VIBRANT for macular edema secondary to retinal vein occlusion; and RADIANCE and MYRROR for myopic choroidal neovascularization, indicated that patients could not only maintain visual acuity but often significantly gain visual acuity despite having severe macular conditions. On average, patients enrolled in these trials could gain one to two lines of visual acuity if treated for wet AMD, two to three lines if treated for macular edema secondary to retinal vein occlusion, two lines if treated for diabetic macular edema and almost three lines if treated for myopic choroidal neovascularization. In general, excellent outcomes could be obtained with different drugs, such as Lucentis (ranibizumab, Genentech/Novartis) and Eylea (aflibercept, Regeneron/Bayer), and with different treatment regimens, either fixed or individualized.

However, as soon as those lessons were translated into routine clinical practice, many of us realized that our patients did not have an improvement in their visual acuity, although the outcomes were still better than the natural history of the disease.

The UK Age-Related Macular Degeneration EMR Users Group looked at real-world ranibizumab treatment of 92,976 injections in 12,951 eyes of 11,135 patients. A loading phase of three monthly injections and an as-needed re-treatment regimen were applied. Real-world visual outcomes achieved in a large number of centers across the United Kingdom did not match the results achieved in most randomized trials, but they were delivered with substantially fewer injections and hospital visits. Initial limited gains in visual acuity (two letters) were not maintained beyond 1 year, with an average of 5.7, 3.7 and 3.7 injections and 9.2, 8.2 and 8.2 visits, respectively, at years 1, 2 and 3.

Similarly, the AURA study evaluated the real-world use of ranibizumab on 2,609 patients in eight countries. After an initial improvement, mean visual acuity declined. The highest improvements in mean visual acuity score and the best maintenance of the visual gain were seen in the United Kingdom, which had among the greatest number of visits (10.2 in year 1) and injections (5.8 in year 1), whereas Italy had an average of 8.5 visits and 3.9 injections during the first year. The LUMINOUS study reported ranibizumab real-world safety and clinical data on 4,444 patients in four countries. In all countries, there was limited improvement in visual acuity from baseline to year 1, and the mean number of injections was low. In the United States, the VERO study showed no difference in mean number of injections in patients treated continuously with ranibizumab (4.9) or aflibercept (5.2) during year 1. Other real-world studies in different countries, such as the LUMIERE study in France and the COMPASS study in Germany, have also demonstrated results inferior to those reported in clinical trials.

We retrospectively analyzed 100 naïve wet AMD eyes treated with as-needed ranibizumab for 12 months. Our results compared unfavorably with those of controlled trials. The number of injections and follow-up visits were 4.8 and 5.1, respectively, and on average there was a two letter visual acuity loss.

Independent of the drug and treatment regimen, it is clear that the number of injections administered to our patients, at least during the first year, is the major driver of the desired optimal outcome. Aggressive individualized as-needed trials with ranibizumab and Avastin (bevacizumab, Genentech/Roche) (CATT, HARBOR) and continuous bimonthly trials with aflibercept (VIEW1, VIEW2) have shown that an average of about seven injections may provide one or more lines of visual acuity improvement in patients with wet AMD. I usually call this the “magic number.” A recently published meta-analysis showed that a “saturation effect” occurs with higher injection frequency, indicating that there is little if any improvement to be gained with additional injections in the first year.

Therefore, one major message is that independent of the regimen and drug chosen, a mean optimum number of injections has been identified and should be respected. The original widely accepted commandment suggesting that we should limit the number of injections with the aim of reducing patient and hospital burden should be promptly disowned. The capacities of our clinics in terms of human resources, spaces, biomedical technologies and electronic medical records need to be updated in the interest of our patients. Countries such as Denmark and Israel, which have greatly invested in the field, have shown a dramatic reduction in AMD-associated blindness thanks to an appropriate use of intravitreal therapies, contemporary interventions in ophthalmology and widely available universal free access to health care.

Finally, with a little help from ophthalmologists, a different, bright world is awaiting our patients.

• References:
• Bloch SB, et al. Am J Ophthalmol. 2012;doi:10.1016/j.ajo.2011.10.016.
• Cohen SY, et al. Retina. 2013;doi:10.1097/IAE.0b013e31827b6324.
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• Gerding H. Klin Monbl Augenheilkd. 2014;doi:10.1055/s-0034-1368241.
• Holz FG, et al. Br J Ophthalmol. 2013;doi:10.1136/bjophthalmol-2013-303232.
• Holz FG, et al. Br J Ophthalmol. 2014;doi:10.1136/bjophthalmol-2014-305327.
• Lanzetta P, et al. Br J Ophthalmol. 2013;doi:10.1136/bjophthalmol-2013-303394.
• Skaat A, et al. Am J Ophthalmol. 2012;doi:10.1016/j.ajo.2011.08.035.
• Wolf A, et al. Graefes Arch Clin Exp Ophthalmol. 2014;doi:10.1007/s00417-013-2562-6.
• Writing Committee for the UK Age-Related Macular Degeneration EMR Users Group. Ophthalmology. 2014;doi:10.1016/j.ophtha.2013.11.031.

• For more information:
• Paolo Lanzetta, MD, OSN Europe Edition Board Member, can be reached at University of Udine, Department of Medical and Biological Sciences, Ophthalmology, 33100 Udine, Italy; +39-0432-21885; email: paolo.lanzetta@uniud.it.

Disclosure: Lanzetta is a consultant to Alcon, Allergan, Bausch + Lomb, Bayer, Lutronic, Novartis, Ophthotech, Roche and Teva.